Restoring Histone Acetylation Accelerates Diabetic Wound Repair by Improving the Spatiotemporal Dynamics of Macrophages

Abstract

Dysregulation of macrophage populations at the wound site is responsible for the non-healing state of chronic wounds. The underlying mechanisms in diabetic conditions at single cell resolution and therapeutic advances remain, however, largely unexplored. Here, it is reported that acetyl histone-H3 (Lys27), an epigenetic mark regulating the macrophage transcriptome, is lost in the hostile tissue microenvironment of diabetes. Diabetic conditions suppress the acetylation of histone, a critical regulator of trained immunity, by activating histone deacetylase (HDAC)-dependent deacetylation pathways. This, in consequence, suppresses STAT1 signaling in macrophages under diabetic conditions. Interestingly, butyrate, a potent HDAC inhibitor, restores the acetyl histone-H3 (Lys27)-dependent transcriptome and thereby effectively rescues macrophage functions even in a persisting diabetic microenvironment. Butyrate not only reinstalls the physiologic STAT1 mediated immune program in macrophages at early phases of diabetic skin repair, but also harmonizes macrophage interactions with keratinocytes and fibroblasts, depicting a unique fingerprint of tissue regeneration. Most interestingly, butyrate breaks the vicious cycle of inflammation in chronic wounds by restoring classical stages of wound healing. This study offers novel pathogenic insight and the unique opportunity to reverse perturbed immune function, holding promise to successfully treat diabetic and other chronic wounds with unresolved inflammation.