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Microglial Priming in Bilirubin-Induced Neurotoxicity

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Abstract

Neuroinflammation is a major contributor to bilirubin-induced neurotoxicity, which results in severe neurological deficits. Microglia are the primary immune cells in the brain, with M1 microglia promoting inflammatory injury and M2 microglia inhibiting neuroinflammation. Controlling microglial inflammation could be a promising therapeutic strategy for reducing bilirubin-induced neurotoxicity. Primary microglial cultures were prepared from 1–3-day-old rats. In the early stages of bilirubin treatment, pro-/anti-inflammatory (M1/M2) microglia mixed polarization was observed. In the late stages, bilirubin persistence induced dominant proinflammatory microglia, forming an inflammatory microenvironment and inducing iNOS expression as well as the release of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β. Simultaneously, nuclear factor-kappa B (NF-κB) was activated and translocated into the nucleus, upregulating inflammatory target genes. As well known, neuroinflammation can have an effect on N-methyl-D-aspartate receptor (NMDAR) expression or function, which is linked to cognition. Treatment with bilirubin-treated microglia-conditioned medium did affect the expression of IL-1β, NMDA receptor subunit 2A (NR2A), and NMDA receptor subunit 2B (NR2B) in neurons. However, VX-765 effectively reduces the levels of proinflammatory cytokines TNF-α, IL-6, and IL-1β, as well as the expressions of CD86, and increases the expressions of anti-inflammatory related Arg-1. A timely reduction in proinflammatory microglia could protect against bilirubin-induced neurotoxicity.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors thank Tan Bin and Meng Shasha for the excellent technical assistance.

Funding

This work was supported by the National Natural Science Foundation (81971426) and the Postgraduate Research Innovation Project of Chongqing (Grant CYB22213).

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Authors and Affiliations

  1. Department of Neonatology Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China

    Hongmei Huang, Siyu Li, Chunmei He & Ziyu Hua

  2. China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, China

    Hongmei Huang, Siyu Li, Yan Zhang, Chunmei He & Ziyu Hua

  3. Chongqing Key Laboratory of Child Infection and Immunity, Chongqing, China

    Hongmei Huang, Siyu Li, Yan Zhang, Chunmei He & Ziyu Hua

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  1. Hongmei Huang
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  2. Siyu Li
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  3. Yan Zhang
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  4. Chunmei He
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  5. Ziyu Hua
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Contributions

Ziyu Hua and Hongmei Huang participated in the design of this study, and they both performed the statistical analysis. Ziyu Hua carried out the study and collected important background information. Hongmei Huang performed the investigation, data collection, and data analysis and drafted the original manuscript. All authors read and approved the final manuscript. Siyu Li and Chunmei He carried out the methodology, literature search, data acquisition, data analysis, and manuscript preparation. Yan Zhang provided assistance for resources, data acquisition, data analysis, and statistical analysis. Ziyu Hua and Yan Zhang performed manuscript review. All authors have read and approved the content of the manuscript.

Corresponding author

Correspondence to Ziyu Hua.

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Rats were purchased from Experimental Animal Center of Chongqing Medical University (License No. SYXK Chongqing 2018–0003), and the experimental process was strictly in accordance with the Chinese Measures for the Use and Management of Experimental Animals.

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Huang, H., Li, S., Zhang, Y. et al. Microglial Priming in Bilirubin-Induced Neurotoxicity. Neurotox Res 41, 338–348 (2023). https://doi.org/10.1007/s12640-023-00643-6

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