Physiol Rep. 2026 Sep;14(19):e71119. doi: 10.14814/phy2.71119.
ABSTRACT
Macrophages are major contributors to inflammatory responses in acute kidney injury (AKI) and rapidly alter their gene expression through epigenetic regulation. This study focused on ASXL1, a chromatin modifier regulating histone marks consisting of H3K27me3 (repressive) and H3K4me3 (activating) in M1 macrophages. We found that ASXL1-positive M1 macrophages were significantly increased in the unilateral ischemia-reperfusion injury kidneys of male mice in the acute phase. In cultured M1 macrophages, RNA sequencing revealed that Asxl1 knockdown upregulated inflammatory response genes such as Il6 and Il1b. Conversely, the expression of anti-apoptotic genes Csf3 and Lcn2 was suppressed, and pathways related to interleukin-17 signaling and Fcγ receptor-dependent phagocytosis were downregulated. In co-culture experiments, Asxl1 silencing in M1 macrophages induced more severe apoptosis and reduced proliferation of mouse renal cortical tubular cells. Mechanistically, chromatin immunoprecipitation analysis demonstrated that Asxl1 knockdown significantly decreased H3K27me3 levels at the Il6 and Il1b promoter regions and H3K4me3 levels at the Csf3 and Lcn2 promoter regions in M1 macrophages. These findings indicate that ASXL1 suppresses excessive inflammatory cytokine expression and preserves anti-apoptotic activity through histone modifications, while maintaining phagocytic capacity in M1 macrophages. ASXL1 in M1 macrophages thus attenuates inflammatory activation and macrophage-mediated renal tubular cell damage in AKI.
PMID:42817046 | DOI:10.14814/phy2.71119