Granzyme B contributes to extracellular matrix degradation in UV‐treated skin (1046.1)

Abstract

Extracellular matrix (ECM) degradation is a hallmark of many chronic inflammatory diseases that can lead to a loss of function, aging and disease progression. Granzyme B (GzmB), a serine protease that is expressed by a variety of cells, has been shown to accumulate in the extracellular space during chronic inflammation and cleave a number of ECM proteins. Using a model of UV‐induced chronic inflammation in the skin, we hypothesized that GzmB contributes to ECM degradation through both direct cleavage of ECM proteins and indirectly through the induction of other proteinases, which leads to a phenotype of aged skin. Wild‐type and GzmB‐knockout (KO) mice were repeatedly exposed to minimal erythemal doses of solar simulated UV‐irradiation for up to 20 weeks. GzmB expression was significantly increased in wild‐type treated skin compared to controls. GzmB deficiency significantly protected against the formation of wrinkles and the loss of dermal collagen density, which was related to the cleavage of decorin, an abundant proteoglycan involved in collagen fibrillogenesis and integrity. GzmB also cleaved fibronectin, and fibronectin fragments have been shown to increase the expression of collagen‐degrading matrix metalloproteinases (MMPs) in fibroblasts. Collectively, these findings indicate a significant role of GzmB in ECM degradation, which may have implications in many chronic inflammatory diseases.Grant Funding Source: Supported by CIHR