ALKBH5 demethylates the m <sup>6</sup> A modification of SOCS3 in microglia/macrophages and alleviates neuroinflammation after brain injury
Abstract
Microglia/macrophage-induced neuroinflammation plays a crucial role in the progression of traumatic brain injury (TBI). However, the involvement of N6-methyladenosine (m 6 A) RNA modifications in this process remains elusive. Single-cell RNA sequencing (scRNA-seq) and m 6 A RNA immunoprecipitation sequencing (MeRIP-seq) across multiple time points postinjury revealed a strong correlation between m 6 A modifications and genes enriched in microglia/macrophages. Furthermore, the m 6 A demethylase ALKBH5 was identified as a key regulator of dynamic m 6 A 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 m 6 A 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–m 6 A–SOCS3 regulatory axis that mitigated microglia/macrophage-driven neuroinflammation after TBI, underscoring its potential as a therapeutic intervention target for TBI progression.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (22)
Lin Cai
Department of Neurosurgery, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Yuqing Liang
Department of Neurosurgery, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Xiaoyu Li
Runxi Fu
Department of Pediatric Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research
Xingyu Niu
Department of Neurosurgery, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Yuxiao Jin
Department of Neurology, Zhongshan Hospital, Laboratory Animal Center, Ministry of Education Frontiers Center for Brain Science, Fudan University
Yuxin Li
Yuheng Zhang
National Children’s Medical Center, Children’s Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, Ministry of Education Frontiers Center for Brain Science, Ministry of Education Innovative Center for New Drug Development of Immune Inflammatory Diseases, Shanghai Key Laboratory of Gene Editing and Cell Therapy for Rare Diseases, Fudan University
Pei Ouyang
National Children’s Medical Center, Children’s Hospital, Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, Ministry of Education Frontiers Center for Brain Science, Ministry of Education Innovative Center for New Drug Development of Immune Inflammatory Diseases, Shanghai Key Laboratory of Gene Editing and Cell Therapy for Rare Diseases, Fudan University
Chen Wang
Qiuyuan Gong
Department of Neurosurgery, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Yang Yang
Lai Wei
Yao Jing
Department of Neurosurgery, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Dianxu Yang
Department of Neurosurgery, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Zhiming Xu
Department of Neurosurgery, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Fang Yuan
Jun Ding
Hao Chen
Bo Peng
Yanxia Rao
Department of Neurology, Zhongshan Hospital, Laboratory Animal Center, Ministry of Education Frontiers Center for Brain Science, Fudan University
Hengli Tian
Department of Neurosurgery, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine