Targeting senescence-associated secretory phenotype macrophage: apigenin inhibits DOT1L-dependent H3K79me2 at IL1A to fight SASP in senescent macrophages

IntroductionApigenin (API) has been utilized in the treatment of atherosclerosis. Senescent macrophages exhibit a senescence-associated secretory phenotype (SASP), which plays a critical role in the progression of atherosclerosis. IL1A expression is thought to be involved in the transition of macrophages to the SASP phenotype. This study explored the effect of API on the atherosclerosis-related SASP in macrophages and the underlying mechanism.MethodsMacrophages were treated with different concentrations of API. The expression of DOT1-like histone lysine methyltransferase (DOT1L) was manipulated in macrophages. Stimulation with lipopolysaccharide (LPS) was conducted to induce the SASP. Macrophage senescence was detected by senescence-associated-β-galactosidase staining. The expressions of interleukin 1 α (IL1A), DOT1L, and markers related to senescence, the SASP, and inflammation in macrophages were assessed. Chromatin immunoprecipitation was performed to check DOT1L-mediated H3K79me2 enrichment at the promoter of IL1A.ResultsAPI treatment effectively reduced cellular senescence in LPS-exposed macrophages. Furthermore, it downregulated markers associated with senescence, SASP, and inflammation, while upregulating the anti-inflammatory cytokine IL-10. Moreover, LPS-induced DOT1L and H3K79me2 enrichment at the IL1A promoter, as well as DOT1L and IL1A upregulation in macrophages, were hindered by API. DOT1L overexpression counteracted API’s effects, including its ability to inhibit senescence, downregulate senescence/SASP/inflammation markers, upregulate IL-10, and prevent H3K79me2 and DOT1L binding at the IL1A promoter. DOT1L silencing reduced LPS-induced senescence, SASPs, and H3K79me2 enrichment in macrophages.ConclusionAPI inhibits DOT1L-mediated H3K79me2 enrichment to downregulate IL1A, thus reducing the SASP of macrophages.