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METTL3 promotes microglial inflammation via MEF2C in spinal cord injury

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Abstract

Spinal cord injury (SCI) is a significant contributor to disability in contemporary society, resulting in substantial psychological and economic burdens for patients and their family. Microglia-mediated inflammation is an important factor affecting the nerve repair of SCI patients. N6-methyladenosine (m6A) is a prevalent epigenetic modification in mammals, which shows a strong association with inflammation. However, the mechanism of m6A modification regulating microglia-mediated inflammation is still unclear. Here, we observed that METTL3, a m6A methylase, was increased in SCI mice and lipopolysaccharide (LPS)-exposed BV2 cells. Knockdown of METTL3 inhibited the increased expression of iNOS and IL-1β induced by LPS in vitro. Subsequently, MEF2C, myocyte-specific enhancer factor 2C, was decreased in SCI mice and LPS-exposed BV2 cells. Knockdown of MEF2C promoted the expression of iNOS and IL-1β. Sequence analysis showed that there were multiple highly confident m6A modification sites on the MEF2C mRNA. METTL3 antibody could pull down a higher level of MEF2C mRNA than the IgG in RNA binding protein immunoprecipitation assay. Knockdown of METTL3 promoted MEF2C protein expression and MEF2C mRNA expression, accompanied by a reduced m6A modification level on the MEF2C mRNA. Knockdown of MEF2C inhibited the anti-inflammatory effect of METTL3 siRNA. Our results suggest that METTL3 promotes microglia inflammation via regulating MEF2C mRNA m6A modification induced by SCI and LPS treatment.

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Author notes

  1. Dongliang Wang and Wei Qian are contributed equally in this study.

Authors and Affiliations

  1. Department of Spinal Surgery, Yancheng First People’s Hospital, Yancheng, 224006, China

    Dongliang Wang

  2. Department of Infectious Diseases, Yancheng Third People’s Hospital, Yancheng, 224051, China

    Wei Qian

  3. Department of Orthopedics, Yancheng First People’s Hospital, Yancheng, 224006, China

    Duanrong Wu, Ya Wu, Kun Lu & Guoyou Zou

Authors
  1. Dongliang Wang
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  2. Wei Qian
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  3. Duanrong Wu
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  4. Ya Wu
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  5. Kun Lu
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  6. Guoyou Zou
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Contributions

Conceptualization, Guoyou Zou; Investigation, Dongliang Wang, Wei Qian, Duanrong Wu, Ya Wu and Kun Lu; Project administration, Guoyou Zou; Visualization, Dongliang Wang; Writing-review & editing, Dongliang Wang and Wei Qian.

Corresponding author

Correspondence to Guoyou Zou.

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All animal experiments were proved by the Animal Care Ethics and Use Committee of Yancheng First People's Hospital.

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Wang, D., Qian, W., Wu, D. et al. METTL3 promotes microglial inflammation via MEF2C in spinal cord injury. Cell Tissue Res 395, 189–197 (2024). https://doi.org/10.1007/s00441-023-03855-6

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