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

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A schematic illustration depicts the UTX/MMP-3 epigenetic regulatory axis governing macrophage senescence to mediate the regenerative niche for regulating angiogenesis and functional recovery after SCI. • Trauma induced macrophages exhibits a cellular senescence after SCI • KDM6A/MMP-3 epigenetic axis governs macrophage senescence. • Epigenetic regulatory axis mediates the regenerative niche for SCI repair. • 3. MMP-3 could propagate cellular senescence in endothelial cells. 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. To investigate the role and underlying mechanism of Ubiquitously transcribed tetratricopeptide repeat X chromosome (UTX) in regulating macrophage senescence following SCI. 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; UTX flox/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. 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. Our findings elucidate the KDM6A/MMP-3 epigenetic regulatory axis, which governs macrophage senescence and shapes a pro-regenerative microenvironment after SCI. Targeting this pathway promotes angiogenesis and facilitates neural repair, highlighting its potential as a therapeutic target for improving functional recovery after SCI.

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