Pharmacological blockade of HDAC3 accelerates diabetic wound healing by regulating macrophage activation

Here, we report the effect of histone deacetylase 3 (HDAC3) inhibition associated with macrophage activation, IL-1β expression, angiogenesis and wound healing in diabetic mice. To determine the expression of HDAC3 in diabetic mice wounds, hyperglycemia was induced in C57BL/6 mice with streptozotocin followed by induction of 6 mm wounds. To understand the effect of HDAC3 selective inhibitor, BG45, wound tissues were isolated for analysing M1/M2 markers expression, immune cells infiltration, angiogenesis and healing factors expression. CD11b+F4/80+ cells were sorted from the wound tissues and analysed for the expression of M1/M2 markers using RT-qPCR and flow cytometer. In cell based assays, HDAC3 expression was measured in macrophages stimulated with high glucose (HG) plus LPS. Macrophages treated with BG45 and HG + LPS were analysed for the expression of pro-IL-1β, mature IL-1β, oxidative stress and pro-inflammatory (M1) and anti-inflammatory (M2) factors. HDAC3 was found to be upregulated in impaired diabetic mice wounds and in macrophages stimulated with HG + LPS. Topical application of BG45 loaded gel accelerated the wound healing in diabetic mice and was evident by improved expression of Collagen-1A, IL-10, TGF-β, and angiogenesis (CD31, VEGF). BG45 treatment decreased the expression of IL-1β, TNF-α, and IL-6 (M1 phenotype), reduced oxidative stress and promoted the expression of Arginase-1 and YM1/2 (M2 phenotype) in macrophages treated with HG + LPS. BG45 also improved the expression of CD11b+F4/80+CD206+ cells in wound tissues and reduced expression of inflammatory markers. HDAC3 is upregulated in diabetic mice wounds and HDAC3 selective inhibitor promotes the wound healing by regulating macrophage activation, angiogenesis and IL-1β. •HDAC3 is upregulated in diabetic mice wounds and in macrophages stimulated with high glucose plus LPS•BG-45 accelerated the wound healing with improved levels of collagen, VEGF, CD31, TGF-β and promoted expression, reduced expression of IL-1β•BG-45 reduced M1 markers and promoted expression of M2 markers in macrophages in-vitro and in diabetic wounds