Proceedings of the National Academy of Sciences of the United States of America · 2025
ALKBH5 demethylates the m6A modification of SOCS3 in microglia/macrophages and alleviates neuroinflammation after brain injury.
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Cai Lin, Liang Yuqing, Li Xiaoyu, Fu Runxi, Niu Xingyu, Jin Yuxiao, Li Yuxin, Zhang Yuheng, Ouyang Pei, Wang Chen, Gong Qiuyuan, Yang Yang, Wei Lai, Jing Yao, Yang Dianxu, Xu Zhiming, Yuan Fang, Ding Jun, Chen Hao, Peng Bo, Rao Yanxia, Tian Hengli
Аннотация
Microglia/macrophage-induced neuroinflammation plays a crucial role in the progression of traumatic brain injury (TBI). However, the involvement of N6-methyladenosine (m6A) RNA modifications in this process remains elusive. Single-cell RNA sequencing (scRNA-seq) and m6A RNA immunoprecipitation sequencing (MeRIP-seq) across multiple time points postinjury revealed a strong correlation between m6A modifications and genes enriched in microglia/macrophages. Furthermore, the m6A demethylase ALKBH5 was identified as a key regulator of dynamic m6A patterns at the injury site. ALKBH5 suppression in microglia/macrophages exacerbated neuroinflammation in vitro and worsened neurological deficits in controlled cortical impact (CCI) models. MeRIP-qPCR and RNA pull-down assays revealed SOCS3 was a downstream target of ALKBH5-mediated m6A demethylation. This demethylation stabilized Socs3 mRNA and enhanced its protein expression, which in turn suppressed neuroinflammation via inhibiting the JAK2-STAT3 pathway. Conversely, SOCS3 depletion impaired functional recovery after injury. These findings unveiled a critical ALKBH5-m6A-SOCS3 regulatory axis that mitigated microglia/macrophage-driven neuroinflammation after TBI, underscoring its potential as a therapeutic intervention target for TBI progression.