Abstract
The four core histones H2A, H2B, H3, H4, and the linker histone H1 primarily bind DNA and regulate gene expression within the nucleus. Evidence collected mainly from the peripheral tissues illustrates that histones can be released into the extracellular space by activated or damaged cells. In this article, we first summarize the innate immune-modulatory properties of extracellular histones and histone-containing complexes, such as nucleosomes, and neutrophil extracellular traps (NETs), described in peripheral tissues. There, histones act as damage-associated molecular patterns (DAMPs), which are a class of endogenous molecules that trigger immune responses by interacting directly with the cellular membranes and activating pattern recognition receptors (PRRs), such as toll-like receptors (TLR) 2, 4, 9 and the receptor for advanced glycation end-products (RAGE). We then focus on the available evidence implicating extracellular histones as DAMPs of the central nervous system (CNS). It is becoming evident that histones are present in the brain parenchyma after crossing the blood-brain barrier (BBB) or being released by several types of brain cells, including neurons, microglia, and astrocytes. However, studies on the DAMP-like effects of histones on CNS cells are limited. For example, TLR4 is the only known molecular target of CNS extracellular histones and their interactions with other PRRs expressed by brain cells have not been observed. Nevertheless, extracellular histones are implicated in the pathogenesis of a variety of neurological disorders characterized by sterile neuroinflammation; therefore, detailed studies on the role these proteins and their complexes play in these pathologies could identify novel therapeutic targets.
Introduction
Nomenclature and intracellular activity of histones
Histones organize chromatin by binding DNA and are among the most conserved eukaryotic proteins. H2A, H2B, H3, and H4 are the core histones that form octamers, which DNA then wraps around. These nucleoprotein complexes, called nucleosomes, produce the “beads on a string” appearance of chromatin under an electron microscope (Silk et al. 2017). The distance between nucleosomes is determined by the binding of linker histones – H1 in humans and mice – to the intervening DNA. H1 pulls adjacent nucleosomes closer together, resulting in tighter chromatin packing (Fyodorov et al. 2018). Additionally, post-translational methylation, acetylation, phosphorylation, and other modifications of the highly cationic tail regions of core histones can influence the tightness of their binding to DNA (Fenley et al. 2018). Modifications of the core histones and binding of H1 to DNA strands are two critical factors regulating gene expression by controlling the availability of DNA to the transcription machinery (Hoeksema et al. 2016). Furthermore, several histone variants exist beyond the core canonical histones (Martire and Banaszynski 2020). These variants are involved in the specialized regulation of nucleosome stability, DNA repair, replication, and transcription. There are also nonnuclear isoforms, which can exist within the cytosol or on the surface of the cell in the form of membrane-bound receptors (Hamilton et al. 2021; Talbert and Henikoff 2021; Tovich et al. 2004). Of note, a proteomic analysis of human and murine histone variants indicates that all their isoforms are highly conserved between species (El Kennani et al. 2018). For the purposes of this review, we will refer to the canonical nuclear histone isoforms unless otherwise specified. Although all histones are cationic, it is important to note that they can be separated into fractions based on the relative abundance of arginine and lysine residues in their structures: H1 makes up the lysine-rich fraction, while H2A and H2B are slightly lysine-rich, and H3 and H4 form the arginine-rich fraction (Marsman et al. 2016; Tagai et al. 2011; Th’ng et al. 2005; Weihe et al. 1978). In the literature, unseparated mixtures of core and linker histones are called either unfractionated or whole histones.
Extracellular activity of histones
While histones are best known for their functions within the nucleus, they can be released into the extracellular space. Wu et al. (2002) first demonstrated that histones H1, H2A, H2B, H3, and H4 were released from apoptotic chromatin of three different tumor cell lines. Subsequently, Zeerleder et al. (2003) reported elevated plasma levels of nucleosomes in patients with severe sepsis and septic shock, which they attributed to involvement of apoptotic processes in these pathologies. Later, Xu et al. (2009) used in vitro and in vivo models of sepsis to demonstrate that extracellular histones contributed to endothelial dysfunction, organ failure, and death of experimental animals exposed to inflammatory challenge. They identified extracellular H3 and H4 as key contributors to sepsis and reported protective actions of anti-histone antibodies and activated protein C, a serine protease that cleaved histones and reduced their cytotoxicity. Extracellular release of histones has since been observed under various conditions involving cell damage or death (Chen et al. 2014; Huang et al. 2015; Kang et al. 2014; Kutcher et al. 2012).
Extracellular histones can exist as individual DNA-free proteins or as components of nucleosomes. They are also an element of neutrophil extracellular traps (NETs), which are composed of chromatin and antimicrobial proteins. Once released into the extracellular space, histones can act as damage-associated molecular patterns (DAMPs), initiating or exacerbating inflammatory responses in various tissues (Silk et al. 2017; Xu et al. 2009; Zeerleder et al. 2003). A substantial body of evidence indicates that the immunostimulatory effects induced by DNA-free extracellular histones are markedly different from those triggered by DNA-bound histones found in nucleosomes or NETs (reviewed by Marsman et al. 2016). In addition, controversy exists related to the cytotoxic actions ascribed to DNA-bound and DNA-free histones. Thus, Abrams et al. (2013a) report direct toxicity of purified calf thymus histones towards human endothelial cell line, which is not observed when isolated nucleosomes are used, unless they are degraded by brief sonication. Low cytotoxicity of nucleosomes towards cardiomyocytes has also been reported by Vogel et al. (2015). Meanwhile, calf thymus nucleosomes have been shown to induce necrotic death of cultured murine lymphocytes (Decker et al. 2003). The role of post-translational modifications of histones, such as methylation and citrullination, on the release of NETs and extracellular histones, as well as their immunogenicity, is another emerging area, which will require future studies (reviewed by Szatmary et al. 2018).
Histones have been identified in circulation following widespread inflammation and tissue damage. Elevated serum histone levels are observed in patients with traumatic injuries, sepsis, and organ failure (Abrams et al. 2013b; Allam et al. 2014; Wen et al. 2016). Moreover, histone levels positively correlate with severity of injury and inflammation, risk of multiple organ failure, and mortality (Kutcher et al. 2012; Silk et al. 2017) while intravenous administration of histones induces organ failure and mortality in mice (Kawai et al. 2016), which may indicate their pathological roles. Most of the evidence concerning the functions and role of extracellular histones in pathological processes has been collected by studying peripheral tissues and pathologies (refer to Section: DAMP-like activity of histones in the periphery). However, it remains unclear whether extracellular histones contribute to pathologies of the central nervous system (CNS) (refer to Section: Extracellular histones in the CNS).
Peripheral and CNS DAMPs
Innate immunity is the first line of host defense. When activated by invading pathogens, the innate immune system launches an inflammatory response, which is immediate and non-specific. The immune system recognizes pathogens by identifying their distinct structures known as pathogen-associated molecular patterns (PAMPs) (Medzhitov 2007). Similar to pathogen-induced inflammation, sterile inflammation can occur when tissue damage or cellular stress leads to the release of endogenous molecules known as DAMPs or alarmins. A group of receptors generally referred to as pattern recognition receptors (PRRs) mediates cellular responses to both PAMPs and DAMPs. PRRs are found on a broad range of cells in both the periphery and the CNS, including dendritic cells, macrophages, microglia, and neurons (Land 2015b; Venegas and Heneka 2017). When sequestered intracellularly, DAMPs cannot be recognized by the innate immune system, but once released into the extracellular space by an injured or stressed cell, they can bind to PRRs. Activation of immune cell PRRs by PAMPs or DAMPs induces the production of a cascade of proinflammatory molecules, including cytokines and chemokines, causing the recruitment of other immune cells, and thus amplifying the inflammatory response (Chen and Nuñez 2010; Roh and Sohn 2018).
It must be emphasized that inflammation is a vital physiological process, which is required for the elimination of infectious pathogens, removal of damaged cells, and tissue repair (Land 2015a). Nonetheless, if inflammation is unresolved and becomes chronic, overproduction and excessive release of DAMPs occurs, transforming inflammatory responses from helpful to harmful (Chen and Nuñez 2010). Thus, pathological roles of inflammation are demonstrated in a very extensive range of cardiovascular, metabolic, rheumatic, and neurodegenerative disorders (Hotamisligil 2006; Roh and Sohn 2018). Numerous endogenous molecules are shown to promote neuroinflammation by acting as DAMPs. They include molecules that typically reside in the nucleus (e.g., high-mobility group box 1 protein [HMGB1], interleukin [IL]-33), the mitochondria (e.g., adenosine triphosphate [ATP], cytochrome c), or the cytosol (e.g., S100 proteins, cyclophilin A) (Chen and Nuñez 2010; Klegeris 2021; Nanini et al. 2018; Roh and Sohn 2018). Several DAMPs contribute to various pathologies, such as Alzheimer’s disease (AD), which is the most common neurodegenerative disorder in the elderly (Venegas and Heneka 2017). One of the hallmark proteins of AD, the extracellular plaque-forming amyloid-beta (Aβ), is considered a DAMP contributing to the pathogenesis of this disease (Clark and Vissel 2015). HMGB1 is another example of a prototypical DAMP (Ito 2014). This protein is normally located in the nucleus where it acts as a DNA chaperone and regulates numerous processes involving chromatin; however, once expelled into the extracellular space, HMGB1 can promote neuroinflammation by activating microglia, the resident CNS immune cells, as well as astrocytes, which are known to produce diverse inflammatory mediators in addition to their homeostasis-supporting functions (Venegas and Heneka 2017). Notably, activated microglia and astrocytes can also release HMGB1, which further sustains inflammatory processes (Gülke et al. 2018). Based on their known DAMP-like effects in peripheral tissues, extracellular histones may elicit neurodegeneration in a manner similar to other, more established CNS DAMPs (Fang et al. 2010; Lue et al. 2001).
Histones as resolution-associated molecular patterns
There is also an emerging group of molecules that possess anti-inflammatory activity and assist in the resolution of inflammation. Similar to DAMPs, they are released by injured cells, but are termed resolution-associated molecular patterns (referred to by some authors as RAMPs) since they counteract inflammation induced by PAMPs and DAMPs (Shields et al. 2011; Wenzel et al. 2020). Several small heat-shock proteins (HSPs) that normally reside in the cell cytoplasm, including αB-crystallin and HSP70, have anti-inflammatory properties once released extracellularly, and are thus proposed to belong to the family of resolution-associated molecular patterns (Klegeris 2021; Shields et al. 2011; Wenzel et al. 2020). For example, astrocytes extracted from αB-crystallin knock-out (KO) mice after induction of experimental autoimmune encephalomyelitis (EAE) demonstrate elevated secretion of the pro-inflammatory cytokine IL-6 when compared to astrocytes from wild-type (WT) animals with EAE (Ousman et al. 2007). Therefore, astrocytic αB-crystallin may abrogate EAE-mediated neuroinflammation, which is indicative of its resolution-associated molecular pattern-like activity. Additionally, clinical studies show that treatment with intravenous αB-crystallin induces a statistically significant decrease in the volume of active lesions in relapsing-remitting multiple sclerosis (MS) (van Noort et al. 2015). Furthermore, one of the main protective functions of extracellular HSP70, another resolution-associated molecular pattern, in AD is the upregulation of Aβ phagocytosis by microglia, which inhibits the formation of Aβ plaques and precludes Aβ from acting as a DAMP (Wenzel et al. 2020). This review summarizes the DAMP-like activity of extracellular histones in the peripheral tissues and evaluates their possible neuroprotective or neurotoxic functions in the CNS as either resolution-associated molecular patterns or DAMPs, respectively.
Extracellular release of histones in peripheral tissues
Histones are released extracellularly by peripheral cells that undergo programmed or unprogrammed death (Murao et al. 2021). Even though other forms of cell death have been defined (Yan et al. 2020), below we summarize evidence linking the extracellular release of histones to three cell death modalities – apoptosis, necrosis, and NETosis – as the most studied mechanisms. In addition, histones can be actively secreted by living cells without the involvement of cell death pathways (Nair et al. 2018). All five main histone subtypes, H1, H2A, H2B, H3, and H4, are detectable in the extracellular space where they may be complexed with DNA as part of nucleosomes, and/or with other nuclear proteins, such as HMGB1. Alternatively, due to their water-soluble nature, individual histones may move around the extracellular space unbound from other macromolecules (Alhamdi et al. 2015; Chen et al. 2015; Silk et al. 2017; Zeerleder et al. 2003). Of note, the available relevant studies may not clearly distinguish between the extracellular presence of DNA-free histones and nucleosomes because the antibodies typically utilized for histone detection are relatively ineffective at discriminating between the two forms (Silk et al. 2017).
Histone release associated with apoptosis
Apoptosis is a form of programmed cell death that is part of homeostatic and immune defense mechanisms (Elmore 2007; Renehan et al. 2001). According to the histone code hypothesis, post-translational modifications to histones alter chromatin structure, and subsequently, gene expression by the host cell (Chen et al. 2014; Füllgrabe et al. 2010). Notably, apoptotic signals induce a unique pattern of histone post-translational modifications, characterized by hyperphosphorylation, acetylation, and methylation, which contribute to the degree of chromatin condensation and degradation. During apoptosis, DNA fragmentation, mediated by caspase-activated DNase I, leads to the dissociation of core and linker histones from the nucleosomes (Chen et al. 2014; Keith Watson et al. 1995; Wu et al. 2002). Cytoplasmic membrane blebs form in the early phase of apoptosis and actin-myosin contractions facilitate the translocation of nuclear histones to these blebs (Wickman et al. 2013). During the late stages of apoptosis, the blebs dissociate from the membrane and form apoptotic bodies, which then discharge histones into the extracellular space. Wickman et al. (2013) demonstrate that apoptotic murine fibroblasts release all five histone types by engaging this blebbing mechanism since the concentration of extracellular histones is downregulated by the inhibition of actin-myosin contractions. Furthermore, upon induction of apoptosis, human lymphocyte, leukocyte, and monocyte cell lines passively release nucleosomes from microparticles, which are small membrane-bound vesicles (Ullal et al. 2011).
That said, histones and nucleosomes are not always released into the extracellular environment after translocation from the cell nucleus to the plasma membrane (Marsman et al. 2016). During apoptosis of several human and murine cell types, including T-lymphocytes, leukocytes, and fibroblasts, nucleosomes and histones remain associated with the cell surface due to their positive charge and the resulting strong binding with the anionic phospholipids of the plasma membrane (Radic et al. 2004; Rekvig et al. 1987; Silk et al. 2017; Wu et al. 2002). Fürnrohr et al. (2007) characterize the specific interactions between histones and the plasma membrane by designing synthetic liposomes to model the phospholipid composition of apoptotic blebs and bodies. Their study measures the individual binding affinities of each histone type to the different species of phospholipids composing the liposomes.
Phosphatidylcholine (PC) is primarily present in the outer leaflet of the plasma membrane while phosphatidylserine (PS) and phosphatidylethanolamine (PE) are more abundant in the inner leaflet. H2A interacts strongly with all three of the above phospholipids. Conversely, H2B has the weakest overall binding affinity to the phospholipids. The remaining histones, H1, H3, and H4, bind most strongly to PE, PC, and PS, respectively (Fürnrohr et al. 2007).
Histone release associated with necrosis
Necrosis is a form of unprogrammed cell death during which the cell membrane ruptures and the intracellular contents leak into the extracellular space. Necrosis occurs in the absence of chromatin fragmentation, activation of intracellular nucleases, or controlled vesiculation that characterizes apoptosis (Fink and Cookson 2005; Gaipl et al. 2004). It is well established that necrotic murine and human cells release DNA-free histones, as well as chromatin and nucleosomes (Allam et al. 2012, 2013; Huang et al. 2011; Jahr et al. 2001; Kang et al. 2014; Ou et al. 2015). Once in the extracellular space, chromatin exerts potent DAMP-like activity; however, its cytotoxicity can be both up- and down-regulated by various enzymatic degradation mechanisms. For example, factor VII activating protease can cleave chromatin released by necrotic human monocytes, thereby producing the more cytotoxic free H1 (Gaipl et al. 2004). Alternatively, a mouse model of myocardial infarction demonstrates that necrotic cells discharge chromatin into the serum. An intravenous injection of DNase I promotes the survival of cardiomyocytes by degrading chromatin into nucleosomes, which are less cytotoxic than intact chromatin (Vogel et al. 2015).
Histone release associated with NETosis
In addition to their release as DNA-free proteins and components of nucleosomes during apoptosis and necrosis, all histones except H1 are part of NETs. NETs are chromatin fibers adorned with neutrophil antimicrobial granular proteins, such as cathepsin G, elastases, myeloperoxidase, and neutrophil protease 4 (Papayannopoulos et al. 2010; Stapels et al. 2015). Under inflammatory conditions, neutrophils are recruited to the sites of infection or tissue damage where they eject their histone-containing NETs (Brinkmann et al. 2004; Huang et al. 2015; Kumar et al. 2015; Papayannopoulos et al. 2010). NETs function as part of the innate immune defense to capture and neutralize extracellular microbial pathogens; however, these complexes can also exacerbate inflammatory cascades by inducing the release of additional DAMPs from neighbouring cells (Denning et al. 2019; Kaplan and Radic 2012). Classically, NETosis has been considered a specific neutrophil cell death mechanism associated with the release of NETs. However, the definition of NETosis has been expanded to include vital NETosis, which involves the expulsion of NETs by neutrophils that do not later undergo cell death. Therefore, NETosis has been categorized into two distinct subtypes, depending on the engagement of cell death pathways (Murao et al. 2021).
Suicidal NETosis, more commonly referred to simply as NETosis, can last several hours, and culminates in the death of neutrophils (Mesa and Vasquez 2013). This mechanism requires nicotinamide adenine dinucleotide phosphate (NADPH)-dependent production of reactive oxygen species (ROS) and an influx of calcium into the cells (Denning et al. 2019; Manda et al. 2014). The increased intracellular concentration of ROS and calcium activates peptidylarginine deiminase 4 (PAD4), which citrullinates arginine residues in the tail regions of core histones, leading to chromatin decondensation and the subsequent aggregation of histones, DNA, and granular proteins into NETs (Neeli et al. 2008; Papayannopoulos et al. 2010; Szatmary et al. 2018). Furthermore, ROS-dependent neutrophil granule enzymes contribute to NET formation and extracellular release of chromatin by cleaving the nuclear envelope, cytoskeletal elements, and chromatin itself. These enzymes also activate the protein gasdermin D, which forms cell membrane pores, allowing NETs to escape into the extracellular space (Metzler et al. 2011; Papayannopoulos et al. 2010; Vorobjeva and Chernyak 2020).
Alternatively to suicidal NETosis, vital NETosis, which is a less established mechanism, does not result in neutrophil death or the disruption of their membrane integrity (Clark et al. 2007; Yipp et al. 2012). During this process, NETs are first encapsulated in vesicles budding from the nuclear membrane (Byrd et al. 2013; Pilsczek et al. 2010). The nuclear vesicles are then transported to the cell membrane and finally released extracellularly (Pilsczek et al. 2010; Vorobjeva and Chernyak 2020). This form of NETosis is not dependent on ROS or granule enzymes, and can occur within minutes (Manda et al. 2014; Yipp and Kubes 2013). Of note, the Nomenclature Committee of Cell Death discourages the use of the term “NETosis” in association with processes that do not result in cell death, such as vital NETosis, which only involves NET extrusion (Galluzzi et al. 2018). Nevertheless, an alternative term for the process of vital NETosis has not been established yet.
Both suicidal and vital NETosis can be induced by a plethora of stimuli, including bacteria, viruses, yeasts, parasites, nuclear DAMPs, ROS, and cytokines (de Buhr and von Köckritz-Blickwede 2016; Szatmary et al. 2018). For example, human neutrophils release histone-containing NETs in response to stimulation with IL-8, lipopolysaccharide (LPS), or phorbol 12-myristate 13-acetate (Brinkmann et al. 2004). Furthermore, cell types other than neutrophils, such as mast cells, basophils, eosinophils, and macrophages, can secrete chromatin mesh-like structures that resemble NETs (Goldmann and Medina 2012; Yousefi et al. 2008). For example, human mast cells, in the presence of bacterial species such as Pseudomonas aeruginosa, Streptococcus aureus, or Streptococcus pyogenes, can release mast cell extracellular traps, which are composed of histones, DNA, tryptase, and anti-microbial peptides (von Köckritz-Blickwede et al. 2008).
Active release from cells
Histones can be released independently of cell death processes; however, these mechanisms are not well established and require further characterization. As mentioned above, live neutrophils can secrete histones within NETs during vital NETosis (Manda et al. 2014; Vorobjeva and Chernyak 2020). Furthermore, the active release of DNA-free histones is suggested by Nair et al. (2018), who demonstrate this phenomenon for LPS-stimulated murine bone marrow-derived macrophages (BMDM). Of note, the secretion of histones occurs in the absence of hallmark apoptotic and necrotic processes, implying that these cell death pathways are not engaged. In addition to releasing free soluble histones, LPS-stimulated BMDMs secrete vesicles where histones are both attached to their extracellular surface and sequestered within (Nair et al. 2018).
Contribution of extracellular histones to peripheral pathologies
After their release from peripheral cells, histones can enter circulation. Low levels of histones and nucleosomes are present in the serum under physiological conditions, but their concentrations increase as a result of numerous pathological conditions characterized by cell damage and death (Ekaney et al. 2014; Phan et al. 2018). DNA-free histones, nucleosomes, and NETs are detectable in the sera of patients with acute organ injuries, autoimmune conditions, and inflammatory disorders (Abrams et al. 2013b; Araki and Mimura 2017; Chen et al. 2014; Decker et al. 2005; Li et al. 2021; Wen et al. 2016; Zeerleder et al. 2003). In cases of traumatic injury, the levels of circulating nucleosomes peak before those of circulating free histones (Abrams et al. 2013b; De Meyer et al. 2012). This may indicate that histones initially enter circulation as part of nucleosomes, and then are released from the nucleosomes as free proteins (Iba et al. 2014). Elevated serum histone concentrations of critically injured adult trauma patients positively correlate with the severity of the injury, occurrence of multiple organ failure, and mortality (Kutcher et al. 2012). Similarly, high levels of nucleosomes in the sera of pediatric trauma patients positively correlate with the severity of the injury and coagulopathy (Russell et al. 2018). Pretreatment of subjects with anti-histone antibodies, heparin, or polysialic acid has been shown to neutralize the extracellular DAMP-like and cytotoxic effects of histones in mouse models, as has pretreatment of extracellular histones with activated protein C (Allam et al. 2013; Huang et al. 2011; Saffarzadeh et al. 2012; Wen et al. 2016; Wildhagen et al. 2014; Xu et al. 2009). Endothelial injury, vascular barrier breakdown, and microvascular thrombosis, along with activation of immune cells, have been identified as key pathogenetic mechanisms triggered by circulating histones, nucleosomes, and NETs. These processes contribute to several different pathologies, including sepsis, trauma, and acute respiratory distress syndrome, which may lead to damage observed in the lung, heart, liver, kidney as well as the brain (for recent reviews see Karki et al. 2020; Li et al. 2021; Sun et al. 2019; Szatmary et al. 2018; Villalba et al. 2020). For example, circulating histones have been shown to be major mediators of cardiac injury in sepsis patients (Alhamdi et al. 2015) and in murine models of sepsis, where whole histones damage cardiomyocytes in vitro and induce heart dysfunction in vivo (Kalbitz et al. 2015). The same study demonstrates these adverse events are attenuated by anti-histone antibodies.
Based on this evidence and the results of clinical studies detailed above, neutralization of circulating and extracellular histones has been suggested as a therapeutic strategy for the treatment of severe inflammation and trauma in peripheral tissues (Chen et al. 2014; Li et al. 2021; Szatmary et al. 2018). Future studies are required to elucidate the entire range of pathophysiological conditions associated with elevated concentrations of circulating extracellular nucleosomes and histones, as well as the mechanisms by which they are released.
DAMP-like activity of histones in the periphery
The prevailing view in the literature is that extracellular histones act as DAMPs due to the predominantly proinflammatory effects they have on various cell types in the periphery. Like many other DAMPs, histones interact with PRRs, including several different toll-like receptors (TLRs), and the receptor for advanced glycation end-products (RAGE) (Table 1) (Allam et al. 2012; Huang et al. 2011, 2013; Qaddoori et al. 2018; Roh and Sohn 2018; Semeraro et al. 2011). Additionally, substantial evidence indicates that histones directly bind to the anionic molecules of the cell membrane, such as phospholipids, teichoic acids, cardiolipins, and polysaccharides (Hariton-Gazal et al. 2003; Rosenbluh et al. 2005). By way of these two main mechanisms, histones can trigger apoptosis and necrosis, as well as contribute to the induction of cytokine secretion and the production of ROS by specific cell types. Peripheral cell receptors and membrane components that mediate the DAMP-like activity of histones are highlighted below.
DAMP-like activity of extracellular histones and histone-containing complexes.
| Receptor/target | Histone subtype/complex | Cell/tissue type | Effect | Reference |
|---|---|---|---|---|
| TLR4 | H2B | Rat PC12 neuron-like cells | Induces cell death and abnormal morphology in cells manipulated to overexpress TLR4 | Munemasa (2020) |
| H2B | Murine retinal microglia | Upregulates IL-1β, TNF, TGF-β, and MCP-1 and induces RGC death | Munemasa (2020) | |
| H4 | Human THP-1 monocytic cells | Upregulates intracellular CXCL10 | Westman et al. (2015) | |
| Whole histones | Primary human leukocytes | Pre-incubation with anti-TLR4 antibodies reduces IL-6 production | Abrams et al. (2013b) | |
| Whole histones | Heparinized human blood cells | Pre-incubation with anti-TLR4 antibodies reduces CXCL10 secretion | Westman et al. (2015) | |
| Whole histones | Murine bloodstream | Upregulate CXCL10, IL-6, IL-10, and TNF and recruit leukocytes to site of injection in WT, but not TLR4 KO mice | Westman et al. (2015) | |
| H4 | Murine lung tissue | Increases severity of chlorine gas-induced ARDS in WT, but not TLR4 mice | Zhang et al. (2020) | |
| H3 | Primary human endothelial cells | A TLR inhibitor abolishes histone-induced membrane permeability and proinflammatory activation | Kim et al. (2022) | |
| TLR2 | Whole histones | Primary human erythrocytes | Pre-incubation with anti-TLR2 antibodies reduces caspase-3 activity, eryptotic cell death, and levels of intracellular ROS and calcium | Yeung et al. (2019) |
| TLR2 and TLR4 | H3 and H4 | Human platelets | Pre-incubation with anti-TLR2 or anti-TLR4 antibodies reduces platelet activation | Carestia et al. (2013) |
| H4 | Murine plasma | Increases TNF and IL-6 in WT, but not TLR2 and TLR4 double KO mice | Allam et al. (2012) | |
| H4 | Primary murine BMDCs | Increases caspase 1 cleavage and IL-1β secretion in WT, but not TLR2 and TLR4 double KO cells | Allam et al. (2013) | |
| Whole histones | Murine PECs | Pre-incubation with anti-TLR2 and anti-TLR4 antibodies leads to downregulation of CD44 and Wilms’ tumor 1 protein (markers of PEC activation) | Kumar et al. (2015) | |
| Whole histones | Murine macrophages and BMDCs | Pre-incubation with anti-TLR2 and anti-TLR4 antibodies downregulates TNF expression | Kumar et al. (2015) | |
| Whole histones | Human platelets | Pre-incubation with anti-TLR2 antibodies, TLR4 antibodies, or their combination, reduces the number of activated platelets and thrombin concentration | Semeraro et al. (2011) | |
| Whole histones | Murine vascular endothelial cells | Pre-incubation with anti-TLR2 antibodies, anti-TLR4 antibodies, or their combination reduces expression of pro-thrombotic tissue factors | X. Yang et al. (2016) | |
| TLR9 | H3 and H4 | Primary murine Kupffer cells | TLR9 antagonist decreases histone-induced ROS production, caspase-1 activation, and release of IL-1β and IL-18 | Huang et al. (2013) |
| H4 and CpG DNA | Murine BMDCs | Increase IL-1β secretion in WT, but not TLR2 and TLR4 double KO cells | Allam et al. (2013) | |
| Whole histones and CpG motifs | Murine liver nonparenchymal cells | Increase IL-6 mRNA in WT, but not TLR9 KO mice | Huang et al. (2011) | |
| P. falciparum polynucleosomes | Primary murine dendritic cells | Increase TNF and IL-12 secretion in WT, but not TLR9 KO cells | Gowda et al. (2011) | |
| TLR4 and TLR9 | Whole histones | Murine liver lobes | NETosis is downregulated in TLR4 KO mice, TLR9 KO mice, and most significantly in TLR4 and TLR9 double KO mice | Huang et al. (2015) |
| RAGE | Whole histones and DNA | Murine peritoneal macrophages and murine BMDMs | Pre-incubation with RAGE silencing RNA decreases IL-1β and HMGB1 | Kang et al. (2016) |
| nDCs | Primary murine macrophages and macrophage-like cell | Upregulate Akt-dependent TNF secretion and oxidative stress-dependent apoptosis and necrosis | Chen et al. (2015) | |
| Phospholipid heads | H1 | Bovine BBB epithelial tissue | Crosses BBB by absorptive-mediated transcytosis | Pardridge et al. (1989) |
| H1, H2A, and H2B | Human umbilical cord vein endothelial cells | Elicit Weibel-Palade body exocytosis | Michels et al. (2016) | |
| Whole histones | Human pulmonary microvascular endothelial cells | Induce influx of extracellular calcium | Allam et al. (2013) | |
| Nucleosomes | Primary human neutrophils | Increase CD11b/CD66 expression, IL-8 secretion, and phagocytic activity | Rönnefarth et al. (2006) | |
| NETs | Human vascular SMCs | Induce apoptosis of SMCs | Silvestre-Roig et al. (2019) |
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ARDS, acute respiratory distress syndrome; BBB, blood brain barrier; BMDC, bone marrow-derived dendritic cell; BMDM, bone marrow-derived macrophage; CD, cluster of differentiation; CpG, deoxycytidyl-phosphate-deoxyguanosine; CXCL, C–X–C motif chemokine ligand; DAMP, damage-associated molecular pattern; HMGB1, high-mobility group box 1 protein; IFN, interferon; IL, interleukin; KO, knock-out; MCP, monocyte chemoattractant protein; nDC, nuclear damage-associated molecular pattern complex; NET, neutrophil extracellular trap; PEC, parietal epithelial cell; RAGE, receptor for advanced glycation end-products; RGC, retinal ganglion cell; ROS, reactive oxygen species; SMC, smooth muscle cell; TGF, transforming growth factor; TLR, toll-like receptor; TNF, tumor necrosis factor-α; and WT, wild-type.
Receptor-dependent effects of histones
TLR4
TLR4 activation is implicated in a variety of inflammatory conditions, including asthma, atherosclerosis, irritable bowel syndrome (IBS), myocarditis, psoriasis, rheumatoid arthritis, sepsis, and systemic lupus erythematosus (SLE) (Gao et al. 2017; Kuzmich et al. 2017; Y. Yang et al. 2016). This receptor is primarily expressed by myeloid and endothelial cells (Sabroe et al. 2002; Vaure and Liu 2014). TLR4 recognizes numerous PAMPs, most notably the bacterial endotoxin LPS (Leitner et al. 2019). TLR4 also binds select DAMPs, such as calcium-binding proteins S100A8/S100A9, HSP70, HMGB1, and histones (Luong et al. 2012; Ma et al. 2017). Histone-induced TLR4 activation leads to the release of several proinflammatory mediators.
Whole human histones induce primary human leukocytes to secrete IL-6, a process which is highly dependent on the influx of extracellular calcium (Abrams et al. 2013b). Incubation of these cells with high concentrations of anti-TLR4, but not anti-TLR2, antibodies, only partially diminishes the secretion of IL-6, indicating the potential involvement of other receptors besides TLR4 in this cellular response. Furthermore, levels of IL-6 in sera from patients with severe nonthoracic blunt trauma correlate significantly with circulating histone concentrations. This clinical finding may indicate that the high levels of IL-6 that are detectable shortly after the onset of trauma are partially a result of the histone-induced secretion of this cytokine by leukocytes (Abrams et al. 2013b).
Westman et al. (2015) demonstrate that whole bovine calf thymus histones induce human heparinized mixed blood cells to release a wide range of chemokines and cytokines, including C–X–C motif chemokine ligand (CXCL)9, CXCL10, C–C motif ligand (CCL)3, CCL7, CCL10, interferon (IFN)-γ, IL-6, IL-8, and tumor necrosis factor-α (TNF). Since the histone-induced expression of CXCL10 by human cells has not been previously explored, subsequent experiments in this study focus on this chemokine. The researchers determine that pretreatment with anti-TLR4, but not anti-TLR2, antibodies, inhibits the whole histone-induced secretion of CXCL10 by the human heparinized blood cells. In addition, whole bovine calf thymus histones induce CXCL10 expression by human THP-1 monocytes. Since it is established that extracellular H4 interacts with diverse cell types, such as endothelial cells, platelets, and erythrocytes (Semeraro et al. 2014; Westman et al. 2014), Westman et al. (2015) further elucidate the interactions of this particular histone with individual receptors. Specifically, they demonstrate that human H4 binds the TLR4/myeloid differentiation factor (MD)-2 complex on human THP-1 monocytes to elicit the production of intracellular CXCL10. In a more recent study, Kim et al. (2022) demonstrate that human recombinant H3 and H4 induce permeability and proinflammatory activation of human endothelial cells. They further show that the H3-induced dysfunction of endothelial cells is abolished by the TLR4 inhibitor CLI-095, but not the TLR2/6 inhibitor CU-CPT-22.
The role of TLR4 in histone-induced inflammatory processes is further supported by in vivo experiments. An intravenous injection of whole calf thymus histones triggers the CXCL10-mediated recruitment of leukocytes to the site of injection in WT, but not TLR4 KO, mice, establishing the role of TLR4 in histone-mediated inflammation (Westman et al. 2015). Furthermore, the WT mice exposed to a sublethal dose of whole histones have elevated levels of the proinflammatory mediators IL-6, IL-10, and TNF in their sera. Interestingly, this histone-mediated upregulation of cytokines is ameliorated in TLR4 KO mice, but not TLR2 KO mice (Westman et al. 2015). In a recent study, H4 activation of TLR4 is implicated in the development of acute respiratory distress syndrome (ARDS). Zhang et al. (2020) induce acute lung injury by exposing mice to chlorine gas and demonstrate a positive correlation between the serum levels of H4 and the concentration of chlorine. An intravenous injection of H4 prior to gas exposure exacerbates the symptoms of ARDS, whereas pretreatment with anti-H4 antibodies has the opposite, protective effect. Of note, TLR4 KO mice, but not TLR2 KO mice, experience less severe disease outcomes in comparison to their WT counterparts after exposure to chlorine gas. Therefore, it is proposed that therapeutics targeting circulating histones may ameliorate ARDS and similar inflammatory disorders in the periphery (Zhang et al. 2020).
TLR2
TLR2 activation is implicated in numerous inflammatory diseases, such as diabetes, psoriasis, rheumatoid arthritis, Sjogren’s syndrome, SLE, and systemic sclerosis (Liu et al. 2014). This receptor is present on the surface of several peripheral cell types, such as myeloid, lymphoid, and mucosal epithelial cells (Juarez et al. 2010; Komai-Koma et al. 2004; McClure and Massari 2014). Similarly to TLR4, TLR2 recognizes several PAMPs, including LPS, as well as DAMPS, such as HSP70, HPS96, HMGB1, and histones (Asea 2008; Huang et al. 2009; Oliveira-Nascimento et al. 2012). The literature predominantly describes histone-induced activation of TLR2 in concert with TLR4 (refer to the next Section). However, Yeung et al. (2019) demonstrate histone-induced effects, which are mediated by TLR2, but independent of TLR4. In primary human erythrocytes, extracellular whole calf thymus histones elevate the levels of intracellular ROS and calcium, as well as caspase-3 activity, ultimately resulting in eryptotic death. Interestingly, the addition of anti-TLR2, but not anti-TLR4, antibodies partially mitigates the cytotoxicity of histones. This indicates that TLR2, in combination with an unknown secondary mechanism, mediates the effects of extracellular histones on erythrocytes.
Combined actions of TLR2 and TLR4
The DAMP-like activities of select histones can be mediated by parallel actions of TLR2 and TLR4 or may require simultaneous activation of both these receptors. For example, the binding of histones to both TLR2 and TLR4 is required for platelet activation. All known recombinant human histone subtypes can individually bind to human platelets and induce hemostatic, proinflammatory, and clotting responses by engaging extracellular receptor kinase, protein kinase B (Akt), p38 mitogen-activated protein kinase (MAPK), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) (Carestia et al. 2013). The authors hypothesize that histones may also interact with glycosaminoglycans on the surface of platelets as these polysaccharides are known to bind other small, positively charged molecules. H4, and to a lesser degree H3 and H2B, elicits the most potent effects on the human platelets. Interestingly, it is speculated that the exact mechanisms of action of these core histones may differ. Furthermore, the administration of either anti-TLR2 or anti-TLR4 antibodies alone reduces platelet activation by H3 and H4, but not H1, H2A, or H2B. These differences in the interactions of histones with TLRs can be due to the fact that the core histones contain the histone folding motif (Arents and Moudrianakis 1995) and that H3 and H4 have a more similar tertiary structure in the folding region when compared to H2A and H2B (Carestia et al. 2013).
All recombinant histone subtypes, except for H3, can induce TNF and IL-6 secretion by murine bone marrow-derived dendritic cells (BMDCs) (Allam et al. 2012). The microscale thermophoresis binding assay, which detects temperature gradients induced by receptor binding, is used to show that human recombinant H4 interacts directly with human recombinant TLR2 and the TLR4/MD-2 complex in a cell-free experimental system (Jerabek-Willemsen et al. 2014). These histone-receptor interactions are validated by in vivo studies that demonstrate H4 cannot upregulate TNF and IL-6 in plasma of TLR2 and TLR4 double-KO mice (Allam et al. 2012). In a follow-up study, these authors determine that LPS-treated necrotic murine BMDCs release H3 and H4, which are known to trigger IL-1β secretion by this cell type. Cytokine induction by H4 is shown to be dependent on caspase-1 activation, oxidative stress, TLR2, TLR4, and assembly of the nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome (Allam et al. 2013).
Due to the potent procoagulant activity of histones, activation of TLR2 and TLR4 by these proteins is also implicated in inflammation-induced thrombosis. Activated platelets initiate the clotting cascade either by secreting polyphosphates (PolyP) or expressing tissue factor (TF). PolyP is a polymer of orthophosphates and is a well-established activator of clotting factor V, which contributes to the production of thrombin (Morrissey et al. 2012; Smith et al. 2006). Recombinant human histones elevate the levels of thrombin in platelet-rich plasma collected from healthy human subjects by activating platelets to release PolyP (Semeraro et al. 2011). H4, and to a lesser degree H3, is the most potent inducer of thrombin production out of all the histone subtypes. Interestingly, in vitro pretreatment of the platelet-rich plasma with anti-TLR2 or anti-TLR4 antibodies decreases the number of activated platelets and the thrombin concentration in response to exposure to whole human histones; however, the combination of anti-TLR2 and anti-TLR4 antibodies causes the most significant downregulation. These histone-mediated effects are not fully ameliorated by the antibodies, suggesting histones may also interact with cellular targets other than TLR2 and TLR4 (X. Yang et al. 2016).
TF is a transmembrane glycoprotein receptor, expressed on perivascular and epithelial cells, that initiates the coagulation cascade by binding clotting factor VII/VIIa (Grover and Mackman 2018). This receptor modulates the expression and secretion of inflammatory molecules, in addition to inducing apoptosis of endothelial cells. When added to cell culture medium, whole calf thymus histones can induce the expression of TF by primary human vascular endothelial cells and a murine macrophage cell line by engaging the activator protein 1 and NF-κB pathways (X. Yang et al. 2016). Human vascular endothelial cells treated with anti-TLR2 antibodies, anti-TLR4 antibodies, or their combination before exposure to histones express lower levels of TF. The combined application of anti-TLR2 and anti-TLR4 antibodies downregulates TF expression most substantially (X. Yang et al. 2016).
Thrombosis of glomerular capillaries during glomerulonephritis also depends on the interaction of histones with TLR2 and TLR4. Kumar et al. (2015) demonstrate that extracellular whole calf thymus histones activate murine parietal epithelial cells (PECs) in vitro by binding to TLR2 and TLR4. Activation of these receptors is associated with PEC hyperplasia and glomerular crescent formation, which are hallmarks of glomerulonephritis. The same study also determines that cultured murine macrophages and BMDCs secrete TNF in a TLR2- and TLR4-dependent manner when treated with whole calf thymus histones. In vivo, TNF can trigger the formation of microthrombi within murine glomerular capillaries, further contributing to the development of glomerulonephritis. In addition, TNF induces primary murine neutrophil death, and the subsequent release of histones (Kaplan and Radic 2012). Therefore, histones can increase TNF secretion, which in turn further elevates extracellular histone concentrations, generating a positive feedback loop and exacerbating the severity of glomerulonephritis (Kumar et al. 2015).
In a murine model of concanavalin A-induced sterile inflammation leading to fatal liver injury, knocking out TLR2 and TLR4, or pretreating with anti-H3 antibodies, improves the survival rate of the mice (Xu et al. 2011). Levels of proinflammatory mediators, TNF, IL-6, IFN-γ, IL-1β, IL-10, and IL-12p70, are downregulated in the sera of TLR2 KO mice, as well as TLR4 KO mice. Interestingly, a more significant decrease in cytokine production is observed in the TLR4 KO mice, compared to TLR2 KO mice, suggesting that this is the primary receptor engaged by histones. Furthermore, when DNA is immunoprecipitated from the mouse plasma with antibodies against a DNA-histone structural motif, only low levels of H3 remain in the sample. This indicates that the H3 histones may primarily act in complex with DNA in this murine model. Therefore, nucleosomes may mediate hepatocyte death, and subsequent liver failure, by activating TLR2 and TLR4.
TLR9
TLR9 activation may contribute to inflammatory mechanisms in cardiometabolic disorders, EAE, rheumatoid arthritis, and SLE (Hosseini et al. 2015; Yu et al. 2010). TLR9 is present on the membrane of the endosomes of epithelial, endothelial, and mononuclear blood cells, and is a well-established receptor for unmethylated deoxycytidyl-phosphate-deoxyguanosine (CpG) motifs of bacterial and viral DNA (El Kebir et al. 2009; Leifer et al. 2004; McClure and Massari 2014). However, this receptor also interacts with endogenous DNA and HMGB1 (Yu et al. 2010). Histones can bind to the host DNA, as well as to bacterial DNA species, such as the TLR9 agonist CpG DNA, enhancing their inflammatory activity. For example, the binding of DNA to TLR9 results in a marginal increase of IL-6 mRNA expression by murine liver non-parenchymal cells; however, simultaneous treatment with whole calf thymus histones and CpG oligodeoxynucleotides enhances this effect significantly (Huang et al. 2011). Therefore, it is highly likely that extracellular histones have an amplifying effect on the cytotoxicity of host DNA, which also acts as a DAMP once released into the extracellular space. In addition, histones may increase the cytotoxicity of NETs since DNA is the primary component of these complexes, but this effect has yet to be conclusively demonstrated. Conversely, histones released within NETs from primary human and rabbit neutrophils exposed to IL-8 or LPS do not directly induce cell death (Brinkmann et al. 2004). Further research is necessary as the few publications documenting histone contributions to NET cytotoxicity report conflicting results (Hu et al. 2017; Kumar et al. 2015; Saffarzadeh et al. 2012).
TLR9 is implicated in the immune response triggered by Plasmodium falciparum, one of the protozoans responsible for malaria. Gowda et al. (2011) demonstrate that purified polynucleosomes derived from this parasite can upregulate TNF and IL-12 secretion by murine dendritic cells in a TLR9-dependent, but not TLR2-dependent, manner. TLR9 activation by histones and DNA may also mediate liver dysfunction. For example, pretreatment of mice with a TLR9 inhibitor, anti-H3 antibodies or anti-H4 antibodies reduces caspase-1 activity and serum levels of IL-1β and IL-18 in a model of ischemia/reperfusion-induced liver injury (Huang et al. 2013). Furthermore, calf thymus H3 and H4 can induce ROS production in cultured Kupffer cells from WT, but not TLR9 KO, mice, likely by enhancing interactions between free endogenous DNA and TLR9. Allam et al. (2013) further establish the signaling interplay between histones, DNA, and several different types of TLRs. As mentioned above, recombinant human H4 induces IL-1β secretion by BMDCs. Although this effect is mediated by TLR2 and TLR4, CpG DNA can prime H4-induced IL-1β release in TLR2- and TLR4-deficient cells by activating TLR9.
Combined actions of TLR4 and TLR9
Only limited information is available concerning the dual activity of TLR4 and TLR9 in the context of the DAMP-like activity of histones. Huang et al. (2015) suggest there may be an overlap between the signaling pathways activated by these two receptors. NETs form in the sinusoids of liver lobes of mice with liver ischemia/reperfusion injury. As a result, necrotic primary murine hepatocytes release histones that further induce NET formation. While a reduction of NETs is observed in the liver lobes of TLR4 and TLR9 single-KO mice, the most significant decrease of NETs is seen in the TLR4 and TLR9 double-KO mice. Since DNA is the primary ligand of TLR9, it is probable that the DNA component of NETs acts in concert with histones, given that the signaling pathways engaged by TLR4 and TLR9 converge on myeloid differentiation primary response 88 protein (Huang et al. 2015; Kawasaki and Kawai 2014).
Although significant evidence implicates TLR2, TLR4, TLR9, and their combined actions in histone-mediated signaling, other receptors may also be involved. It is speculated that it may be more challenging for nucleosomes, in contrast with the more structurally extensive NETs, which also contain histones and DNA, to simultaneously activate two or more TLRs (Marsman et al. 2016). Thus, the structural disparity between nucleosomes and NETs may be responsible for the noted signaling pathway differences. Decker et al. (2005) report that nucleosomes induce the secretion of IL-6, IL-8, IL-12p40, and TNF by human monocyte-derived dendritic cells (MDDCs) and upregulate the expression of cluster of differentiation (CD)83 and CD86 by MDDCs and purified human myeloid dendritic cells (MDCs). Since MDDCs do not express TLR9 and MDCs do not express TLR2 or TLR4, these authors hypothesize the presence of a ubiquitous nucleosome receptor, which is different from TLR2, TLR4, and TLR9. Several studies demonstrate that mammalian nucleosomes bind to the surface of various human and murine cell types although the specific receptor is not identified (Coritsidis et al. 1995; Hefeneider et al. 1992; Koutouzov et al. 1996). However, it is worth noting that the human and murine TLRs were not discovered until the late 1990s (Vijay 2018). Furthermore, as mentioned previously, nucleosomes derived from P. falciparum can bind TLR9. This indicates that the specific receptors engaged by nucleosomes may be species-dependent (Gowda et al. 2011).
RAGE
Activation of RAGE is associated with a broad array of diseases characterized by inflammation, including cancer, cardiovascular disease, and diabetes (Hudson and Lippman 2018; Ibrahim et al. 2013; Sparvero et al. 2009). RAGE is a 35 kDa transmembrane receptor of the immunoglobulin family that is present at low concentrations on most differentiated adult cells, except for skin and lung epithelial cells which express high levels of this protein (Akirav et al. 2012; Chuah et al. 2013; Sparvero et al. 2009). RAGE engages ligands similar to those that bind TLRs, such as LPS, HMGB1, and histones. This receptor is shown to mediate the upregulation of IL-1β and HMGB1 expression induced by a combination of purified recombinant whole histones and DNA in murine peritoneal macrophages (PMs), as well as in murine BMDMs (Kang et al. 2016). Of note, this increase in IL-1β and HMGB1 is diminished in BMDMs with short hairpin RNA-silenced RAGE, but not TLR2 or TLR4, expression. The downregulation of IL-1β and HMGB1 is also observed in PMs derived from RAGE KO, but not TLR4 KO, mice (Kang et al. 2016).
Histones aggregate with DNA and HMGB1 to form nuclear DAMP complexes (nDCs). In primary murine macrophages and murine macrophage-like cell lines, nDCs bind RAGE to initiate Akt-dependent TNF secretion, as well as oxidative stress-dependent apoptosis and necrosis. Notably, nDCs can elicit these effects without interacting with TLR2 or TLR4 (Chen et al. 2015). This finding indicates that the traditional TLR-dependent DAMP-like signaling activity of extracellular histones may be modified when they are complexed with other DAMPs.
Cell membrane-dependent effects of histones
Anionic plasma membrane components, including phospholipids, teichoic acids, cardiolipin, and LPS, are known to directly bind to the cationic N-terminal tail regions of histones. Such interactions can contribute to the well-documented antimicrobial effects of histones, as well as their cytotoxic activity toward select eukaryotic cells (Allam et al. 2014; Hoeksema et al. 2016; Parseghian and Luhrs 2006; Pereira et al. 1994). In addition, histones may induce destabilization of the cell membrane bilayer and the formation of membrane pores by direct translocation across the cell membrane, as opposed to traditional endocytosis. Recombinant H2A, H3, and H4 can penetrate the lipid bilayers of large synthetically prepared vesicles while H2B can attach to, but not transverse, the lipid layers (Hariton-Gazal et al. 2003). The authors speculate that the inability of H2B to penetrate membranes may be because this histone subtype has the lowest arginine content and thus, demonstrates the weakest interactions with the anionic membrane components. A later study, using human HeLa epithelial and human Colo-205 adenocarcinoma cells, demonstrates that a mixture of recombinant histones is more successful at translocating across the cell membrane than individual histone subtypes, indicating that there may be cooperative binding activity among the histone subtypes that assists their group passage (Rosenbluh et al. 2005). When tested individually, H2A is the most effective of the histone subtypes at migrating across the cell membrane, followed by H4, H3, and finally H2B. Another study determines that H1 can also bind liposomes and that its binding affinity is enhanced by the increased content of the phospholipid PS in liposomes (Zhao et al. 2004). Furthermore, H1-PS complexes can aggregate on the surface of immortalized human T-lymphocytes, also referred to as Jurkat cells. The accumulation of H1-PS complexes disrupts the plasma membranes of T-lymphocytes, leading to the internalization of H1 and subsequent apoptosis.
Extracellular histones show direct toxicity towards pulmonary, hepatic, and cardiac tissues (Alhamdi et al. 2015; Kalbitz et al. 2015; Kawai et al. 2016). After intravenous injection, whole histones induce multiple organ failure in mice. The lungs and liver fail within 15 min due to the direct toxic effects of histones, while the kidneys fail at a much later stage, likely because of histone-triggered systemic inflammation (Kawai et al. 2016). The authors observe that tissue damage is not a result of histone-PRR interactions, but rather an outcome of histones binding directly to plasma membranes of endothelial cells, resulting in pore formation and calcium influx that causes cell death. They postulate that the difference in anionicity of the plasma membranes found at the tissue-blood interfaces of the lungs, liver, and kidneys determines their varied responses to histones. Collier et al. (2019) use isolated murine and human mesenteric arteries to demonstrate extracellular histone-induced endothelial cell damage, which is dependent on the influx of extracellular calcium. This study also employs vascular tissues from transgenic animals to establish that the effects of histones on endothelial cells are independent of transient receptor potential vanilloid 4 channel and TLR4. A similar, receptor-independent effect is demonstrated by Abrams et al. (2013b) who show that whole recombinant human histones bind membrane phospholipids of immortalized human pulmonary microvascular endothelial cells, inducing an influx of extracellular calcium. Notably, pretreatment with anti-TLR2 and anti-TLR4 antibodies does not prevent this calcium entry. Furthermore, a cocktail of calf thymus H1, H2A, and H2B, which are the lysine-rich histones, induces Weibel-Palade body exocytosis by human umbilical cord vein endothelial cells in a charge-, calcium-, and caspase-dependent, but TLR-independent manner, indicating that these histones interact with the membrane phospholipids (Michels et al. 2016). Weibel-Palade bodies are endothelial cell organelles that store and release procoagulant and proinflammatory mediators; therefore, the histone-Weibel-Palade body axis is implicated in the propagation of immunothrombosis (Gould et al. 2015). It should also be noted that in addition to receptor-independent cytotoxicity of histones towards endothelial cells, TLR4-mediated breakdown of endothelial barriers has been observed (Kim et al. 2022).
In addition to endothelial cells, histones can interact with the plasma membranes of other cell types. NETs induce apoptosis of human vascular smooth muscle cells (SMCs), and inhibitors of TLR1, TLR2, TLR3, or TLR4 do not mitigate their cytotoxicity (Silvestre-Roig et al. 2019). This study further demonstrates that recombinant H4 alone triggers immediate lytic death of SMCs by increasing cell membrane permeability. This effect is mediated by the interaction of the positively charged N-terminal domain of H4 with the membrane components of SMCs. However, the pore formation observed by Silvestre-Roig et al. (2019) cannot explain electrical currents provoked by histone exposure in other cell types, such as Ehrlich ascites tumor cells (Gamberucci et al. 1998) and human endothelial cells (Abrams et al. 2013b).
Rönnefarth et al. (2006) demonstrate that purified calf thymus nucleosomes are endocytosed by primary human neutrophils in a TLR2- and TLR4-independent manner, and subsequently elevate CD11b/CD66b expression, IL-8 secretion, and phagocytic activity of these cells. Interestingly, extracellular histones and DNA alone, as well as their combination, fail to induce IL-8 secretion, indicating that this activity is specific to the nucleosome complex. While this suggests that these effects are mediated by direct interactions between nucleosomes and the cell membrane, an unidentified nucleosome-specific receptor may be involved as previously speculated (refer to Section: Combined actions of TLR4 and TLR9). Furthermore, the nucleosome-induced activation of neutrophils delays, but does not prevent, apoptosis of these cells.
Watson et al. (1999) demonstrate that the N-terminal regions of H2A and H2B proteins within purified human nucleosomes interact with heparan sulfate proteoglycans on the surface of a human T-lymphocyte cell line. After nucleosomes initially engage the proteoglycans, the complexes can subsequently bind sulfated polysaccharides located on the plasma membrane, such as heparin and dextran sulfate, to strengthen their interaction with the cell surface. Further research is required to identify the complete spectrum of peripheral cell receptors and membrane components with which circulating extracellular nucleosomes and histones interact, as well as the resulting signaling pathways engaged. In addition, these findings from the periphery may aid in the elucidation of the potential DAMP-like activity of extracellular histones in the CNS, which is less studied and will be discussed below.
Extracellular histones in the CNS
Translocation from periphery to CNS
As previously mentioned, all histone subtypes can translocate across the membranes of epithelial cell lines independently of the endocytic pathway by binding to phospholipids and permeabilizing cell membranes (Abrams et al. 2013b; Hariton-Gazal et al. 2003; Pereira et al. 1994; Xu et al. 2009). Nevertheless, the endothelium of the blood-brain barrier (BBB) is significantly less permeable than the peripheral endothelium due to the increased presence of cell-to-cell tight and adherens junction complexes (Villalba et al. 2020). Free diffusion across the BBB is usually only permissible for low molecular weight (<400 Da) and highly lipid-soluble molecules (Abbott 2013; Pardridge 2012). Histones exceed the molecular weight threshold and are highly cationic, suggesting they are incapable of diffusing across the BBB. To the best of our knowledge, no studies have established that histones can cross the intact BBB in this manner. Extracellular histones utilize various other mechanisms for crossing the BBB to enter the CNS from the peripheral serum, albeit the quantities of histones using these routes are small. Transcytosis, disruption of BBB cell-to-cell junctions, and neutrophil-mediated migration are the main mechanisms used by histones to translocate from the periphery into the CNS.
Transcytosis
Transcytosis is the process of migration where a molecule is endocytosed by one side of the cell, transported through the cell, and finally exocytosed across the membrane on the opposite side (Pulgar 2019). This phenomenon can be receptor- or adsorptive-mediated. Adsorptive-mediated transcytosis is dependent on charged components of the cell membrane, such as clathrin, heparan sulfate proteoglycans, phospholipids, and sialo-glycoconjugates (Hervé et al. 2008). Transcytosis is proposed as one of the mechanisms for histone migration to the CNS. For example, Pardridge et al. (1989) demonstrate that histones are sequestered by BBB endothelial cells in vivo. In this study, carotid artery perfusion is used to introduce radioactively labelled calf thymus H1 to rats. While most of the administered histones that reach the brain are localized to the vasculature, approximately 8% of H1 infiltrates the brain parenchyma, likely by transcytosis across the BBB. Furthermore, radioactively labelled calf thymus H1 can migrate across the epithelial cells of microvessels isolated from the bovine brain, an in vitro model of the BBB, in a time- and temperature-dependent manner (Pardridge et al. 1989). The transcytosis of H1 across microvessels is diminished by incubation at four degrees Celsius, which inhibits the initial endocytosis step. Notably, the binding between H1 and both the luminal and antiluminal surfaces of the brain capillaries is eventually saturable; however, histones can be adsorbed into microvessels at much higher concentrations than other cationic proteins, such as albumin and immunoglobulins. Nevertheless, the interactions of histones with the endothelial lining of the brain microvessels can be partially inhibited by the administration of select polycations, including protamine and polylysine, which compete with histone binding to the phospholipid heads. Overall, this study suggests that H1 migration from the periphery to the CNS occurs by means of adsorptive-mediated transcytosis, enabled by the charge-based interactions between the anionic components of the phospholipid membrane and the cationic histones (Pardridge et al. 1989).
The migration of histones into the CNS may be facilitated by their co-transport with other peripheral DAMPs, such as Aβ peptides and HMGB1. In AD, peripheral Aβ peptides can be transferred across the BBB and into the brain parenchyma. For example, RAGE-mediated transcytosis of Aβ peptides across the BBB is observed (Deane et al. 2003). Since H1 can interact directly with these peptides, the two may be trafficked together across the BBB (Duce et al. 2006). In addition, all histone subtypes can be found in nDCs. nDCs also contain HMGB1, which is known to trigger RAGE-mediated endocytosis (Chen et al. 2015; Kokkola et al. 2005; Yang et al. 2019). Therefore, although this phenomenon has not yet been documented, nDCs released from necrotic cells may cross the BBB via RAGE-mediated transcytosis, thereby carrying circulating histones into the brain parenchyma.
Disruption of BBB
Recent evidence indicates that histones can permeabilize the BBB, likely by reducing the integrity of tight and adherens junctions connecting endothelial cells in brain microvasculature (Moxon et al. 2020; Villalba et al. 2020). For example, monolayers of primary human brain microvascular endothelial cells experience an immediate loss of barrier integrity when treated with whole histones purified from P. falciparum, a protozoan responsible for cerebral malaria (Moxon et al. 2020). Of note, the administration of non-anticoagulant heparin ameliorates this histone-mediated adverse effect. Moxon et al. (2020) observe that all histone subtypes are also present in the serum of pediatric patients with cerebral malaria. Strikingly, this is the first publication to report the presence of histones derived from parasites in human serum as approximately 50% of the circulating histones originate from P. falciparum. The histones localize along the endothelial surface of the cerebral blood vessels and the increased concentration of histones in this region is associated with dysregulated BBB permeability; therefore, plasmodial histones may transmigrate across the BBB into the CNS. Furthermore, in cerebral malaria, protozoa can penetrate the BBB, and thus, may release histones once they have already invaded the CNS (Elsheikha and Khan 2010).
The specific mechanisms of histone-mediated BBB disruption are further elucidated by Villalba et al. (2020). They demonstrate that whole calf thymus histones cause the breakdown of the continuous and ordered anchoring of tight junction proteins in murine brain microvascular endothelial cell monolayers. This histone activity is exacerbated by the increased presence of cholesterol sulfate, which elevates the anionicity of the cell membranes and thereby increases the binding affinity between histones and the cell membrane. This study further demonstrates that an intravenous injection of whole calf thymus histones in mice induces increased, yet reversible, BBB permeability towards small-molecule tracers up to 3 kDa in size. Specifically, the decreased expression of tight and adherens junction proteins is primarily observed in the hippocampus. Interestingly, extracellular histones do not activate astrocytes or microglia, which is a well-established mechanism resulting in leaky brain vasculature. Therefore, the histones disrupt BBB integrity and induce its subsequent permeability to small molecules by dysregulating cell-to-cell junctions Villalba et al. (2020). Further studies are needed to establish whether histones can sufficiently compromise the integrity of the BBB to enable their own migration into the CNS.
Villalba and colleagues also note a remarkable resistance of endothelial cells in cerebral blood vessels to histone-induced toxicity compared to, for example, pulmonary endothelial cells. They further describe brain region-specific adverse effects of circulating histones, which induce reversible leakage of BBB and loss of tight junction protein expression in the hippocampal area, but not cerebral cortex of mice (Villalba et al. 2020). In a separate study, these authors confirm resistance of brain vasculature to histone-induced damage by demonstrating that histone infusion in mice leads to the breakdown of the endothelial barrier of small blood vessels in the kidney and lung, but not in the brain (Villalba et al. 2021, preprint). These observations may indicate that endothelial cells in the microvasculature of the brain, and especially in its hippocampal areas, possess protective mechanism against high levels of circulating histones, but this hypothesis requires experimental proof.
NET-mediated translocation
Neutrophil migration into the brain parenchyma and subsequent NETosis have recently been identified as features of several neurological conditions, such as AD, MS, traumatic brain injury (TBI), and neuropsychiatric lupus, indicating that histones are likely found in the extracellular space of diseased and injured brains (DiStasi and Ley 2009; Guo et al. 2021; Pietronigro et al. 2017). Allen et al. (2012) demonstrate that primary murine neutrophils migrate across a monolayer of murine brain endothelial cells. The transmigrated neutrophils that are collected and then transferred onto primary murine cortical neurons release NETs, resulting in significant death of these neurons. Conversely, unmanipulated naive neutrophils do not exhibit neurotoxicity towards primary murine cortical neurons, which indicates that neutrophils adopt an inflammatory phenotype during or after transmigration (Allen et al. 2012).
These findings are further supported by in vivo experiments. In murine models of AD, Aβ peptides, as well as IL-1, are shown to attract neutrophils to the surface of the brain endothelium (Allen et al. 2012; Zenaro et al. 2015). Neutrophil extravasation across the BBB is mediated by the integrin, lymphocyte function-associated antigen 1, expressed by neutrophils, and its ligand, intercellular adhesion molecule 1, expressed by brain endothelial cells (DiStasi and Ley 2009; Zenaro et al. 2015). The highly reactive neutrophils have a relatively short half-life within the CNS, which suggests that these cells may undergo NETosis soon after transmigration (Pietronigro et al. 2017). In a murine model of ischemia induced by electrocoagulation of the middle cerebral artery, neutrophils infiltrate the brain parenchyma following BBB disruption and release their NETs into the periinfarct region (Kang et al. 2020). Neutrophils can further invade the perivascular space of cortical arterioles from the leptomeningeal vessels as detected in another murine model of permanent ischemia induced by cauterization of the middle cerebral artery (Perez-de-Puig et al. 2015). Interestingly, extracellular DNA and citrullinated H3, which are hallmarks of NETosis, are not detectable in the cerebral vasculature until 24 h after induction of ischemia. Furthermore, Perez-de-Puig et al. (2015) observe infiltrating neutrophils within the perivascular spaces of cerebral arteries and, to a lesser extent, within the infarcted parenchyma of post-mortem brain tissue from stroke patients. Of note, this study does not attempt to examine the presence of NETs in the post-mortem brain tissue; therefore, additional research is required to ascertain the behaviour of infiltrating neutrophils, and subsequent release of histone-containing NETs, resulting from stroke, AD, and other human neurological disorders.
Release from CNS cells
Emerging data indicate that neurons and glial cells can release histones into the extracellular space. All five of the main histone subtypes, H1, H2A, H2B, H3, and H4, are detectable in the extracellular spaces of the human and murine CNS; however, the mechanisms by which histones are released, specifically under pathophysiological conditions, require further elucidation (Table 2) (Schutzer et al. 2010; Simoes et al. 2020).
Pathophysiological conditions or their model systems and stimuli associated with the release and activity of extracellular histones in the CNS.
| Cell type | Pathophysiological condition/stimulant | Histone subtype | Reference | |
|---|---|---|---|---|
| Neurons | Murine neurons | AD model | H1 | Duce et al. (2006) |
| Murine hippocampal and thalamic neurons | Scrapie | H1 | Bolton et al. (1999) | |
| Human neurons | AD | H1 | Bolton et al. (1999) | |
| Human SH-SY5Y neuroblastoma | MPP+ | H2A, H3, H4 | Park et al. (2016) | |
| Human midbrain dopaminergic neurons | PD | H2A, H3, H4 | Park et al. (2016) | |
| Astrocytes | Human astrocytes | AD | H1 | Bolton et al. (1999) |
| Human 1321N1 astrocytoma | LPS-induced NLRP3 inflammasome activation and pyroptosis | H4 | Sun et al. (2019) | |
| Rat hippocampal astrocytes | LPS-induced sepsis | H4 | Sun et al. (2019) | |
| Microglia | Primary murine microglia | Apoptosis | H3 | Klein et al. (2014) |
| Murine BV2 microglia | Apoptosis | H3 | Klein et al. (2014) | |
| Murine BV2 microglia | LPS | All histone subtypes | Woo et al. (2017) | |
| Murine BV2 microglia | LPS and IFN-γ | All histone subtypes | Woo et al. (2017) | |
| Mixed cell cultures | Primary murine astrocytes and microglia | LPS and IFN-γ | H2A and H2B | Jeon et al. (2010) |
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AD, Alzheimer’s disease; CNS, central nervous system; IFN, interferon; LPS, lipopolysaccharide; NLRP3, nucleotide-binding domain (NOD)-like receptor protein 3; MPP+, 1-methyl-4-phenylpyridinium; and PD, Parkinson’s disease.
Histone release from neurons
Human SH-SY5Y neuroblastoma cells upregulate the expression of H2A, H3, and H4 after exposure to 1-methyl-4-phenylpyridinium (MPP+), a parkinsonism-inducing neurotoxin (Park et al. 2016). This study also documents an upregulation of these three histone subtypes in the cytosol of dopaminergic neurons extracted from the midbrain of Parkinson’s disease (PD) patients. Furthermore, H1 is present in the cytosol of neurons and astrocytes localized to Aβ plaques in brain tissue extracted from a murine model of AD (Duce et al. 2006). Although the mechanism of histone translocation from the nucleus to the cytosol in these cell types remains unknown, the presence of histones in the cytosol may mark the initial steps of their extracellular release. Alternatively, it may indicate vesicular trafficking of histones to the plasma membrane, since H1 is present on the surface of human neurons and astrocytes (Bolton et al. 1999). Interestingly, this study detects the nonnuclear isoform of H1. As previously mentioned, there are histone variants besides the canonical histones that exist primarily outside of the nucleus. Nonnuclear H1 is not a constituent of the nucleosome but instead is permanently bound to the plasma membrane where it primarily binds extracellular LPS. Bolton et al. (1999) also demonstrate that immunostaining for nonnuclear H1 in AD brain tissue samples is localized to pathological sites identified by the presence of hyperphosphorylated tau, indicating that the plasma membrane-bound nonnuclear H1 may contribute to AD pathophysiology. These findings corroborate earlier evidence that histones are localized to senile plaques in AD brains (Issidorides et al. 1995). Interestingly, in murine scrapie, the hippocampus and thalamus present similar nonnuclear H1 clustering, which is associated with the death of neurons and activation of glial cells. Of note, the upregulation of extracellular histones is not observed in a murine model of acute neurodegeneration mediated by excitotoxic neuron death following an intrastriatal injection of N-methyl-D-aspartate (NMDA) (Bolton et al. 1999). Therefore, the authors speculate that neuronal injury itself may not be the source of nonnuclear histones in the diseased brain.
Histone release from astrocytes
Immunostaining for H1 is associated with astrocytes in human AD brain tissue (Bolton et al. 1999). Murine oligodendroglioma cells, but not primary rat astrocytes, release H1-enriched microvesicles into the extracellular space, implicating histone secretion in brain tumor pathophysiology (Schiera et al. 2013). Furthermore, Sun et al. (2019) demonstrate that human astrocytoma cells release H4 as a result of LPS-induced NLRP3 inflammasome activation and pyroptosis. The LPS-stimulated astrocytoma cell death and subsequent histone release can be ameliorated by treatment with dexmedetomidine, an α2-adrenoreceptor agonist, which protects cell membrane integrity. This study also determines that elevated release of histones can be attributed to astrocytes in the hippocampus of rats after an intraperitoneal injection of LPS.
Histone release from microglia
There is evidence that, in addition to astrocytes, microglia can also release histones. Jeon et al. (2010) identify low levels of H2A and H2B in the secretome of primary mixed murine glial cells stimulated with a combination of LPS and IFN-γ, but not in the secretome of unstimulated cells. Of note, the mixed cell culture primarily contains astrocytes (∼62%), followed by microglia (∼29%), and then other unidentified cell types (∼9%). Furthermore, low levels of all histone subtypes are detectable in the secretome of murine BV2 microglia stimulated by LPS, or the combination of LPS and IFN-γ (Woo et al. 2017). Cytosolic and membrane-bound H3 are observed in primary and BV2 murine microglia undergoing apoptosis (Klein et al. 2014). Similar observations have yet to be made with human microglia.
Histone release under pathophysiological conditions
To date, only a few studies have been specifically designed to confirm that histones are present in the extracellular space of the human or murine CNS, in either physiological or disease states. For example, a recent proteomics study reveals that all murine histones, which are analogous to human H1, H2A, H2B, H3, and H4, are present in the mouse cerebrospinal fluid (CSF) (Simoes et al. 2020). Furthermore, H1, H2A, H2B, H3, and H4 are also detectable in the CSF samples from healthy human subjects (Schutzer et al. 2010). A recent study demonstrates upregulation of H3 in the CSF of patients after a spinal cord injury, in comparison to normal control subjects (Siddiq et al. 2021). Moreover, in a study of the protein content of hippocampal tissues from AD and age-matched control brains, H2A is upregulated in AD patients as measured by high-performance liquid chromatography/mass spectrometry (Begcevic et al. 2013). Meanwhile, H2B is upregulated in the vitreous humor of patients with acute primary angle closure (APAC) glaucoma (Munemasa 2020). The authors hypothesize that H2B is secreted by hypoxic and dying cells, potentially including iris pigment epithelial cells, ciliary epithelial cells, vascular endothelial cells, as well as retinal glial cells and neurons. Once released into the extracellular space, H2B may activate TLR4 and induce inflammation and death of neurons characteristic of glaucoma.
Potential leakage of histones from the CNS into peripheral blood has also been suggested. For example, elevated levels of nucleosomes are detected in plasma from the retroorbital sinus of mice with cerebral ischemia/reperfusion injury (De Meyer et al. 2012). Laridan et al. (2017) identify H3 within NETs deposited on thrombi extracted from the cerebral vasculature of patients with ischemic stroke. The increased presence of circulating extracellular histones in patients with various neurological disorders indicates that histones may be a candidate biomarker to identify the onset of these diseases and a means to monitor their progression. Nevertheless, future studies are required to elucidate the entire range of neurological conditions in pathophysiological processes in which histones participate.
DAMP-like activity of histones in the CNS
The DAMP-like activity of histones is not well established in the CNS, in comparison to their effects in the periphery (refer to Section: DAMP-like activity of histones in the periphery); however, the evidence summarized below indicates that extracellular histones may modulate select functions of glia and neurons after their release from the brain cells or their migration into the CNS across the BBB (Figure 1). While histones are implicated in several neurological conditions, such as AD, glaucoma, PD, SLE, stroke, and TBI, the literature is conflicting on whether the histone-mediated activity is overall neuroprotective or neurotoxic, due to their resolution-associated molecular pattern- or DAMP-like activity, respectively.
DAMP-like signaling mechanisms of histones in the CNS. Dark and light green receptors represent established and potential molecular targets of histones, respectively. Solid and dotted lines represent establish and potential signaling pathways of histones, respectively.
Effects of extracellular histones on neurons
Several studies demonstrate the direct effects of extracellular histones on neurons, but the results of these studies are inconsistent. Mishra et al. (2010) observe that in vitro administration of all histone subtypes, except H4, triggers neuritogenesis of primary murine cerebellar neurons. Conversely, Gilthorpe et al. (2013) determine that the in vitro treatment with extracellular H1 induces axonal damage in primary murine cortical neurons and that extracellular application of core histones does not affect neuronal viability. Sun et al. (2019) demonstrate that in vitro treatment with whole calf thymus histones induces the death of rat PC12 neuron-like cells. Furthermore, these cells adopt small round morphology with diminished arborization of cellular processes, in comparison to the elongated distal arborization observed in the untreated cell cultures. Interestingly, H2B alone is not cytotoxic toward PC12 cells unless they are manipulated to overexpress TLR4 (Munemasa 2020). Moreover, an intravitreal injection of H2B in mice is neurotoxic to retinal ganglion cells (RGCs), which is accompanied by upregulated phosphorylation of MAPKs and increased concentration of IL-1β, monocyte chemoattractant protein (MCP)-1, transforming growth factor (TGF)-β, and TNF mRNA in the aqueous humor. The H2B-mediated neurotoxicity and upregulation of cytokines are abrogated in TLR4 KO mice (Munemasa 2020).
Bolton et al. (1999) hypothesize that the extracellular nonnuclear H1 released by murine neurons and astrocytes may disrupt the cytoskeletal organization of these cells and bind molecules associated with neurodegeneration, such as extracellular Aβ peptides. Furthermore, the nonnuclear H1 histones are present on the surface of cortical neurons in the brain tissue of rats after an intrastriatal injection of LPS. The nonnuclear H1 histones can complex with LPS, indicating that neurons may express this isoform of H1 in response to bacterial infections (Bolton and Perry 1997). The authors hypothesize that nonnuclear H1 may also cause neurotoxicity in autoimmune disorders where the body produces high levels of autoantibodies against nuclear histones, which may be cross-reactive with the nonnuclear H1. As a result, as shown in SLE, elevated concentrations of anti-H1 antibodies circulate in the peripheral serum and can penetrate the BBB where they may bind nonnuclear H1 on the surface of neurons. The anti-H1 antibody and nonnuclear H1 aggregate in immune complexes, which are neurotoxic and may result in widespread neuronal degeneration; however, this histone-mediated adverse activity has yet to be demonstrated in the human CNS (Bolton and Perry 1997). Therefore, further research must be undertaken to elucidate the direct effects of extracellular histones on neurons, as well as the receptors engaged.
Effects of extracellular histones on glial cells
To the best of our knowledge, only two in vitro studies describe interactions between extracellular histones and glial cells. As previously mentioned, Munemasa (2020) demonstrates that an intravitreal injection of H2B in mice induces deterioration of the RGC layer. Interestingly, the immunofluorescence data indicates that H2B upregulates the expression of TLR4, which is co-localized with inner retinal cells expressing ionized calcium-binding adaptor molecule (Iba)-1, a marker for activated microglia. Therefore, the interaction between H2B and TLR4 on retinal microglia may mediate the death of RGCs and the upregulation of inflammatory cytokines. To date, no other studies have explored the involvement of different receptors, including TLRs, in histone-induced neurotoxicity, glial-mediated or otherwise.
Gilthorpe et al. (2013) show that treatment with extracellular H1 activates primary murine microglia, as indicated by increased surface expression of major histocompatibility complex (MHC) class II molecules. H1 also improves the survival of primary murine microglia in serum-free culture medium and acts as a microglial chemoattractant. In addition, murine cortical astrocytes are activated by extracellular H1, as demonstrated by the widespread induction of stellate morphology. Therefore, H1 may be a potent regulator of both microglia and astrocyte functions; however, this study does not clarify whether glial responses to histones are overall neurotoxic or neuroprotective. It must be emphasized that the response of glial cells towards whole histones, as well as individual subtypes, is still essentially unknown. Furthermore, no studies have attempted to characterize the effects of histones on human glial cells. Thus, histone-mediated regulation of human and murine glial cell functions, including their immune responses, is a knowledge gap that should be addressed by future studies.
Contribution of extracellular histones to CNS pathologies
As implied above (see Section: Histone release under pathophysiological conditions), histones may be involved in a variety of neurological disorders, including AD, PD, stroke, TBI, and glaucoma (Chen et al. 2014). Interestingly, several biochemical studies demonstrate that histones interact with brain pathology-associated proteins, such as Aβ peptides, the secreted amyloid precursor protein, and α-synuclein, suggesting histones may influence the progression of AD or PD (Currie et al. 1997; Duce et al. 2006; Potempska et al. 1993). Additionally, in a mouse model of focal cerebral ischemia induced by middle cerebral artery occlusion, an intravenous injection of anti-H2A/H4 antibodies abrogates extracellular histone-mediated cell death (De Meyer et al. 2012). Conversely, infusion with calf thymus histones after induction of ischemia in this mouse model exacerbates the severity of infarcts and neurological outcomes. In a rat model of sepsis, treatment with LPS increases extracellular H4 concentrations in the hippocampus (Sun et al. 2019). This increase is associated with hallmarks of neuroinflammation, including elevated secretion of IL-1β and IL-18, as well as activation of caspases 1 and 3. Dexmedetomidine ameliorates these histone-mediated effects and prevents neuronal death in a manner similar to its protective activity in vitro mentioned above. A more recent study also demonstrates that in a surgically-induced murine model of TBI, the activation of neutrophil TLR4 after these cells invade the brain parenchyma causes them to eject NETs (Vaibhav et al. 2020); however, nucleosomes, but not NETs, are present in damaged swine cortical brain regions after a similar experimental procedure (Sillesen et al. 2013).
The release of NETs in the CNS is implicated in a diverse set of neurological disorders, including AD, Lyme neuroborreliosis, meningitis, MS, neuropsychiatric lupus, stroke, and TBI (Guo et al. 2021). For example, increased levels of circulating NETs are associated with declining neurological outcomes of patients with TBI (Vaibhav et al. 2020). However, the specific role of histones in the NET-mediated pathophysiology has yet to be elucidated. Nevertheless, the neurotoxic potential of extracellular histones, as well as their proposed involvement in the pathophysiology of various human neurological conditions and their animal models, justifies further research since these proteins could be a target for the diagnosis, prevention, or treatment of these disorders.
Conclusions
In the periphery, it is well-established that extracellular histones behave in a DAMP-like manner by activating RAGE and several different TLRs, as well as by binding directly to the plasma membrane (Table 1). However, additional research is required to elucidate the specific intracellular signaling pathways that are engaged by histones binding to TLRs, RAGE, and cell membrane structures. Since histones are present in the extracellular space unbound to other molecules, but can also form nucleosomes, NETs, and nDCs, interactions of histones with other components of these macromolecular structures and how these interactions affect their DAMP-like activity require further studies.
Unlike the periphery, the activity of extracellular histones in the CNS is largely unknown. Current evidence indicates that histones primarily promote inflammatory mechanisms, although it remains unclear if these proteins are overall protective or harmful to neurons and glial cells (Figure 1). In other words, despite their well-characterized DAMP-like behaviour in the periphery, it remains inconclusive whether histones behave more as resolution-associated molecular patterns or DAMPs in the CNS. Nevertheless, increasing numbers of studies demonstrate the extracellular release of histones by different types of brain cells and their entry into the brain parenchyma across the BBB, especially when its barrier functions are disrupted due to pathological processes (Table 2). Therefore, further studies on the functional consequences of histone release into the extracellular space of the CNS are warranted. Furthermore, to date, TLR4 is the sole receptor to be identified as a mediator of histone effects in the CNS (Munemasa 2020). Therefore, it is paramount that additional receptors, such as TLR2, TLR9, and RAGE, as well as different plasma membrane components are investigated as the potential targets for histone binding within the CNS.
In the future, targeted proteomics studies should be used to identify which histones are present extracellularly in the brains of healthy individuals, as well as patients with various neurological disorders, including AD, MS, PD, sepsis, and severe CNS trauma. Further in vitro and in vivo experiments examining the roles of histones in neurological disease, trauma, and brain homeostasis should also be performed. Such studies would elucidate whether histones play a role in the development or progression of neurodegenerative diseases, in addition to improving our understanding of their role in maintaining healthy CNS functions. Intervening with PRR activation and their downstream signaling is increasingly considered a means of targeting inflammation in a wide variety of neurological disorders. It is possible that the development of small-molecule antagonists of receptors that are activated by histones could reduce their proinflammatory activity and effectively treat the CNS disorders that extracellular histones contribute to. However, it will also be essential to ensure that this approach does not disrupt the physiological roles these receptors play in resolving infections and maintaining brain homeostasis.
Finally, studies with the nonnuclear isoform of H1 should also be performed to determine whether this protein has a unique function in healthy or diseased CNS states. Understanding the role and functions of this protein could be crucial in the development of histone-targeting therapeutics for brain injuries and diseases. For example, if this protein is found to help resolve chronic neuroinflammation or promote brain homeostasis, it is possible that its function could be restored by interfering with the activity of naturally occurring anti-histone antibodies found in patients with autoimmune disorders. This could be a highly novel line of research, as previous and ongoing efforts to therapeutically target extracellular histones have focused on neutralizing the adverse DAMP-like activity of histones themselves. Considering the substantial severity and frequent mortality associated with the DAMP-like activity of histones, as well as their poorly understood functions in the brain, further research clarifying the role histones play in various brain pathologies could lead to novel therapeutic approaches in a broad range of neurological disorders.
Funding source: Grants from the Jack Brown and Family Alzheimer’s Disease Research Foundation, the Natural Sciences and Engineering Research Council of Canada, and the University of British Columbia Okanagan Campus
Acknowledgment
The authors would like to thank all members of the Laboratory of Cellular and Molecular Pharmacology for the helpful discussions and comments on the manuscript.
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Author contributions: All authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
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Research funding: This research was supported by grants from the Jack Brown and Family Alzheimer’s Disease Research Foundation, the Natural Sciences and Engineering Research Council of Canada, and the University of British Columbia Okanagan Campus.
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Conflict of interest statement: The authors declare no conflicts of interest regarding this article.
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