Targeting Dnmt3a/m5C/RelA Axis Attenuates Microglia Inflammatory Response and Improves Postoperative Recovery in Chronic Compressive Cervical Spinal Cord Injury
Source abstract
Abstract
ABSTRACT Chronic compressive cervical spinal cord injury (cCSCI) is a major cause of adult spinal cord dysfunction. Surgical decompression is the primary treatment; however, microglia‐driven neuroinflammation often hampers postoperative recovery. This study was conducted to investigate the role of 5‐methylcytosine (m5C) in sustaining pro‐inflammatory microglial states following decompression. Using a mouse cCSCI model, we performed single‐nucleus RNA sequencing (snRNA‐seq) to map microglial states, calculated an m5C‐regulator activity score, and validated m5C changes via dot blot. We examined the Dnmt3a–RelA pathway in primary microglia through siRNA knockdown, m5C‐RIP, and mRNA stability assays. Therapeutic potential was assessed with intrathecal AAV‐shDnmt3a. SnRNA‐seq revealed a dominant pro‐inflammatory microglial subpopulation (C1) post‐decompression, enriched for NF‐κB signaling. The C1 subset exhibited an elevated m5C score and increased Dnmt3a expression. Dnmt3a knockdown reduced m5C enrichment on RelA transcripts, destabilized RelA mRNA, and suppressed NF‐κB activation. In vitro, Dnmt3a silencing reduced pro‐inflammatory marker expression and cytokine release, and microglia‐targeted AAV‐shDnmt3a improved neurological recovery in cCSCI mice. These findings underscore the potential of targeting the microglia Dnmt3a/m5C/RelA axis to enhance postoperative recovery.
Source: crossref · Quality: baseline
Research context
OpenAlex topics: Spinal Cord Injury Research · Neuroinflammation and Neurodegeneration Mechanisms · Cancer-related gene regulation
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
Affiliations
Division of Spine, Department of Orthopedics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital Southern University of Science and Technology) Shenzhen China
Shenzhen Key Laboratory of Musculoskeletal Tissue Reconstruction and Function Restoration Shenzhen China
Division of Spine, Department of Orthopedics, Changde Hospital, Xiangya School of Medicine Central South University Changde China
Department of Orthopedics, Tianjin Hospital Tianjin University Tianjin China
Department of Trauma Orthopedics, Weifang People's Hospital Shandong Second Medical University Weifang China
Department of Orthopedics, Sun Yat‐sen Memorial Hospital Sun Yat‐sen University Guangzhou China
Department of Biochemistry Homeostatic Medicine Institute School of Medicine Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research Southern University of Science and Technology Shenzhen China
Guangdong Provincial Clinical Research Center for Geriatrics Shenzhen Clinical Research Center for Geriatrics Department of Geriatrics Shenzhen People's Hospital Shenzhen China
Funding
National Natural Science Foundation of China
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