C16 Accelerates Wound Healing by Inhibiting High Glucose Induced Inflammasome Activation in a Mouse Model of Diabetic Wounds

Sustained activation of NALP3 mediated IL-1β identified to be the cause for the delayed wound healing process in diabetes. Depleting NALP3 and IL-1β genes, shown to have restrictions due to their negative impact of angiogenesis inhibition and epidermal cysts formation. Latest research shows that inflammasome activation inhibitors and IL-1β blockers promote the wound healing process in diabetic mice. Alternative to depletion of NALP3 and IL-1β genes, choosing of NALP3 mediated IL-1β blockers using small molecule inhibitors would be better for diabetic wounds. Hence, finding the biomarkers regulating the activation of NALP3 mediated IL-1β synthesis would be interesting as their inhibition may promote the healing. Here we propose Protein Kinase Receptor (PKR) as one of the biomarker which involve in high glucose induced NALP3 activation and IL-1β synthesis in macrophages. We hypothesized that PKR mediated inflammasome activation and IL-1β release in macrophages is one of the cause for delayed diabetic mice wounds. With our research, we found that PKR is up regulated in delayed diabetic mice wounds and in macrophages stimulated with high glucose. Selective inhibition of PKR using C16 decreased the release of proinflammatory factors like NALP3 and IL-1β in macrophages. Topical application of C16 hydrogel promoted the wound healing in diabetic mice by increasing re-epithelization. Similarly C16 application to diabetic mice wounds induced the angiogenesis (PECAM) and fibrotic markers (TGF-β) along with decreasing neutrophils (MPO) and macrophages (F4/80) infiltration. Collagen deposition and tensile strength of the C16 treated wounds observed to be more compared to blank gel treated diabetic mice wounds.