Acetylation State of Histone Core Defines Macrophage Dynamics in Diabetic Wounds

Dysregulation of macrophage populations at the wound site is responsible for the non-healing state of chronic wounds. The molecular mechanisms underlying macrophage dysfunction and its control in diabetes are largely unexplored on an epigenetic level. Here, we report that acetyl histone-H3 (Lys27), an epigenetic mark regulating the macrophage transcriptome, is lost in the hostile tissue microenvironment in diabetes. The diabetic microenvironment, profoundly suppresses the acetylation of histone by activating HDACs-dependent deacetylation pathways. This, in consequence, suppress the STAT1 signaling in macrophages maintained in diabetic conditions. Interestingly, the HDAC inhibitor butyrate - via restoring the acetyl histone-H3 (Lys27)-dependent transcriptome - effectively rescues macrophage functions in a diabetic microenvironment. Butyrate reinstalls the STAT1 mediated transcription program and consequently macrophage activity depicting a unique fingerprint of tissue regeneration and inflammation control even in a hostile diabetic microenvironment. Most interesting, butyrate breaks the vicious cycle of inflammation in diabetic wounds. Our study offers novel pathogenic insight and the unique opportunity to reverse perturbed macrophage function thus holding promise to successfully treat diabetic and other chronic wounds and conditions of unrestrained inflammation.