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4-Octyl Itaconate Attenuates Neuroinflammation in Experimental Autoimmune Encephalomyelitis Via Regulating Microglia

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Abstract

Abnormal activation of microglia, the resident macrophages in the central nervous system, plays an important role in the pathogenesis of multiple sclerosis (MS). The immune responsive gene 1(IRG1)/itaconate axis is involved in regulating microglia-mediated neuroinflammation. 4-Octyl itaconate (4-OI), a derivative of itaconate, plays a crucial immunomodulatory role in macrophages. This study investigated the effects and mechanisms of action of 4-OI on experimental autoimmune encephalomyelitis (EAE) and inflammatory BV2 microglia. In an EAE mouse model, clinical evaluation was conducted during the disease course. Hematoxylin and eosin staining was performed to assess inflammatory infiltration and Luxol Fast Blue was used to visualize pathological damage. Quantitative real-time polymerase chain reaction, western blotting and immunofluorescence were used to evaluate inflammatory response and microglial function status in EAE mice. BV2 microglia were used to further investigate the effects and mechanisms of action of 4-OI in vitro. 4-OI significantly alleviated the clinical symptoms of EAE, the inflammatory infiltration, and demyelination; reduced the levels of inflammatory factors; and inhibited the classical activation of microglia in the spinal cord. 4-OI successfully suppressed the classical activation of BV2 microglia and decreased the levels of inflammatory factors by activating the Nrf2/HO-1 signaling pathway. Furthermore, 4-OI downregulated IRG1 expression in both EAE mice and inflammatory BV2 microglia. 4-OI attenuates the microglia-mediated neuroinflammation and has promising therapeutic effects in MS.

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Funding

This work was supported by the National Natural Science Foundation of China (grant numbers: 81771363); Tianjin Key Medical Discipline (Specialty) Construction Project (grant numbers: TJYXZDXK-004A); Scientific Research Program of Tianjin Municipal Education Commission (grant numbers: 2022KJ244).

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Author notes

  1. Ning Zhao and Ming Yi are co-first author.

Authors and Affiliations

  1. Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China

    Ning Zhao, Lin-Jie Zhang, Qiu-Xia Zhang & Li Yang

  2. Department of The Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, 611731, China

    Ming Yi

  3. Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, Sichuan, China

    Ming Yi

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Contributions

All authors contributed to the study conception and design. Material preparation, experimental operation and data analysis were performed by Ning Zhao, Ming Yi, Lin-Jie Zhang. The first draft of the manuscript was written by Ning Zhao and Ming Yi, and all authors commented on previous versions of the manuscript. All authors reviewed and approved the final manuscript.

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Correspondence to Li Yang.

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All animal experiments were approved by the Ethics Committee of Tianjin Medical University General Hospital (IRB2024-DW-04) and conformed to the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

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Zhao, N., Yi, M., Zhang, LJ. et al. 4-Octyl Itaconate Attenuates Neuroinflammation in Experimental Autoimmune Encephalomyelitis Via Regulating Microglia. Inflammation (2024). https://doi.org/10.1007/s10753-024-02050-1

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