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Nrf2 activator Diethyl Maleate attenuates ROS mediated NLRP3 inflammasome activation in murine microglia

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Abstract

Microglia are the tissue-resident immune cells of the central nervous system. As a part of the innate immune response, NLR Family Pyrin Domain Containing Protein 3 (NLRP3) inflammasome activation leads to cleavage of caspase-1 and triggers secretion of proinflammatory cytokines and may also result in pyroptotic cell death. Inflammasome activation plays a crucial role in inflammatory conditions; aberrant activation of inflammasome contributes to the pathogenesis of neurodegenerative diseases. Diethyl Maleate (DEM) is a promising antiinflammatory chemical to alleviate inflammasome activation. In this study, NLRP3 inflammasome was activated in N9 murine microglia via 1 µg/ml LPS (Lipopolysaccharide) for 4 h and 5 mM ATP (Adenosine 5′-triphosphate) for 1 h, respectively. We demonstrated that 1 h pretreatment of DEM attenuated NLRP3 inflammasome activation in microglial cells. Besides, mitochondrial ROS decreased upon DEM pretreatment in inflammasome-induced cells. Likewise, it ameliorated pyroptotic cell death in microglia. DEM is a potent activator of Nrf2 transcription factor, the key regulator of the antioxidant response pathway. Nrf2 has been a significant target to decrease aberrant inflammasome activation through the antioxidant compounds, including DEM. Here, we have shown that DEM increased Nrf2 translocation to the nucleus, resulting in Nrf2 target gene expression in microglia. In conclusion, DEM is a promising protective agent against NLRP3 inflammasome activation.

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Abbreviations

ARE:

Antioxidant response element

ATP:

Adenosine 5′-triphosphate

ASC:

Apoptosis-associated speck-like protein containing a CARD

bZIP:

Basic-region leucine zipper

CNC:

Cap “n” collar

CNS:

Central nervous system

DEM:

Diethyl Maleate

Gclc:

Glutamate cysteine ligase catalytic subunit

Gclm:

Glutamate cysteine ligase regulatory subunit

HO-1:

Heme oxygenase-1

Keap1:

Kelch-like ECH-associated protein 1

LPS:

Lipopolysaccharide

NF-κB:

Nuclear factor-κB

NLRP3:

NLR family pyrin domain containing protein 3

Nqo1:

NAD(P)H:quinone oxidoreductase 1

Nrf2:

Nuclear factor-erythroid-2-related factor 2

PRR:

Pattern recognition receptor

ROS:

Reactive oxygen species

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Funding

The authors declare that no funds or grants were received during the preparation of this manuscript.

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Authors and Affiliations

  1. Izmir Biomedicine and Genome Center, Dokuz Eylul University Health Campus, Mithatpasa St. 58/5 Balcova, 35340, Izmir, Turkey

    Cagla Kiser, Ceren Perihan Gonul & Sermin Genc

  2. Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir, Turkey

    Cagla Kiser & Ceren Perihan Gonul

  3. Department of Neuroscience, Health Science Institute, Dokuz Eylul University, Izmir, Turkey

    Sermin Genc

Authors
  1. Cagla Kiser
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  2. Ceren Perihan Gonul
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  3. Sermin Genc
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Contributions

CK and CPG conceived the study, performed the experiments. CK analyzed and interpreted the data and wrote the manuscript. SG conceived the study, interpreted the data, and edited the manuscript.

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Correspondence to Sermin Genc.

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Kiser, C., Gonul, C.P. & Genc, S. Nrf2 activator Diethyl Maleate attenuates ROS mediated NLRP3 inflammasome activation in murine microglia. Cytotechnology 76, 197–208 (2024). https://doi.org/10.1007/s10616-023-00609-8

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