Granzyme B as a therapeutic target for wound healing

Introduction: Granzyme B is a serine protease traditionally understood as having a role in immune-mediated cytotoxicity. Over the past decade, this dogma has been challenged, with a new appreciation that granzyme B can exert alternative extracellular roles detrimental to wound closure and remodeling. Granzyme B is elevated in response to tissue injury, chronic inflammation and/or autoimmune skin diseases, resulting in impaired wound healing. Areas covered: This review provides a historical background of granzyme B and a description of how it is regulated. Details are provided on the role of granzyme B in apoptosis as well as newly identified extracellular roles, focusing on those affecting wound healing, including on inflammation, dermal-epidermal junction separation, re-epithelialization, scarring and fibrosis, and autoimmunity. Finally, the use of pharmacological granzyme B inhibitors as potential therapeutic options for wound treatment is discussed. Expert opinion: Endogenous extracellular granzyme B inhibitors have not been identified in human bio-fluids, thus in chronic wound environments granzyme B appears to remain uncontrolled and unregulated. In response, targeted granzyme B inhibitors have been developed for therapeutic applications in wounds. Animal studies trialing inhibitors of granzyme B show improved healing outcomes, and may therefore provide a novel therapeutic approach for wound treatment.