Granzyme K Expressed by Classically Activated Macrophages Contributes to Inflammation and Impaired Remodeling

Granzyme K (GzmK), traditionally described as a pro-apoptotic, granule-secreted serine protease, has been proposedtopromote inflammation. Foundat lowlevels in theplasmaofhealthy individuals, GzmKismarkedly elevated in response to sepsis and infection. In this study we investigated the role of GzmK in inflammation and remodeling in response to thermal injury. In human burn tissue, GzmK was elevated compared with normal skin, with expression predominantly found inmacrophages. GzmKwas expressed and secreted by cultured human classically activatedmacrophages. To assess the role of GzmK in response to skin wounding, wild-type or GzmK(-/-) mice were subjected to grade 2 thermal injury. GzmK(-/-) mice exhibited improved wound closure, matrix organization, and tensile strength compared with wild-type mice. Reduced proinflammatory IL-6, ICAM-1, VCAM-1, and MCP-1 expressions were observed at 3 days after injury. Additionally, GzmK induced IL-6 expression in keratinocytes and skin fibroblasts that was dependent on PAR-1 activation. Re-epithelialization showed the greatest degree of improvement of all healing parameters, suggesting that keratinocytes are sensitive to GzmK-mediated proteolysis. In support, keratinocytes, but not skin fibroblasts, exposed toGzmK showed impaired wound healing in vitro. In summary, GzmK influences wound healing by augmenting inflammation and impeding epithelialization.