Targeting the NOD-Like Receptor Pyrin Domain Containing 3 Inflammasome to Improve Healing of Diabetic Wounds.

Abstract

Significance: Chronic skin wounds are a significant health problem around the world, often leading to amputation and even death. Although persistent inflammation is a hallmark of these poorly healing wounds, few available therapies have been designed to target inflammation. In this review, we summarize available evidence of the role of the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome in impaired wound healing and describe strategies to inhibit the inflammasome to improve wound healing. Recent Advances: The NLRP3 inflammasome plays an important physiological role in skin wound healing, during which transient inflammasome activity contributes to both epidermal and dermal healing. In contrast, sustained activity of the NLRP3 inflammasome leads to impaired epidermal and dermal healing associated with diabetes. Of importance, preclinical studies have demonstrated that inhibiting the NLRP3 inflammasome-induced resolution of inflammation, increased granulation tissue formation and collagen deposition, and accelerated reepithelialization and wound closure. Critical Issues: NLRP3 inflammasome inhibitors have appealing potential for translation into therapies for chronic wounds. Although preclinical studies have shown promising results, there is a need for human/clinical studies to evaluate dosing formulations, potential therapeutic effects, dose-response relationships, and possible side effects. Future Directions: Among strategies to inhibit the NLRP3 inflammasome, glyburide, metformin, peroxisome proliferator-activated receptor agonists, and the dipeptidyl peptidase 4 inhibitor saxagliptin appear to be closest to clinical translation, as these drugs are already Food and Drug Administration approved for other indications. Future clinical studies are needed to develop topical formulations of these drugs, and to assess the safety and efficacy of these inhibitors, to improve healing of chronic wounds.