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; 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.

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 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.