KDM6A/MMP-3 epigenetic axis governs macrophage senescence after spinal cord injury for mediating the regenerative niche to promote neurological repair

INTRODUCTION: Spinal cord injury (SCI) stands as the primary cause of disability, still lacking a clear pathogenesis and effective treatment. The role of macrophages is particularly unclear in SCI, especially regarding cellular senescence. Additionally, the mechanisms driving macrophage senescence after SCI, the release of senescence-associated secretory phenotype (SASP) factors that affect the regenerative niche, and their contributions to SCI progression remain elusive. OBJECTIVES: To investigate the role and underlying mechanism of Ubiquitously transcribed Tetratricopeptide repeat, X chromosome (UTX) in regulating macrophage senescence following SCI. METHODS: A contusive SCI model was constructed to explore the presence of senescent macrophages. After screening for UTX by a PCR array, conditioned knockout UTX mice (LysM-Cre; UTXflox/flox) was constructed to explore the effect of UTX on macrophage senescence to influence angiogenesis and neurological function. Furthermore, RNA-seq and ChIP-seq were carried out to screen the downstream target gene Matrix Metalloprotease-3 (MMP-3). At last, RNA-seq was performed to explore the effect of MMP-3 on endothelial cells in vitro. RESULTS: An elevated presence of lysine demethylase 6A (KDM6A/UTX), a special epigenetic regulatory modifier, was observed in macrophage senescence after SCI. Conditional deletion of UTX not only prevented macrophage senescence, but also enhanced the formation of a regenerative niche that protected endothelial cells from senescence and improved their proliferation. Mechanistically, UTX epigenetically regulated MMP-3 transcription through demethylating histone H3 lysine di/trimethylation (H3K27me2/3) at its promoter region. This led to senescent macrophages releasing MMP-3, a key SASP factor that disrupts the local microenvironment and impairs spinal cord repair post-injury. Notably, MMP-3 could act as a pro-senescent agent by senescent macrophages to propagate cellular senescence in endothelial cells (ECs), exacerbating cellular senescence in the injured region. CONCLUSIONS: Our findings elucidate the KDM6A/MMP-3 epigenetic regulatory axis, which governs macrophage senescence and creates an inhibitory microenvironment for regeneration after SCI. Targeting this pathway promotes angiogenesis and facilitates neural repair, highlighting its potential as a therapeutic target for improving functional recovery after SCI.