title: Granzyme B mediates both direct and indirect cleavage of extracellular matrix in skin after chronic low-dose ultraviolet light irradiation.
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. Ultraviolet light (UV) irradiation from the sun is widely considered as the major cause of visible human skin aging, causing increased inflammation and enhanced ECM degradation. Granzyme B (GzmB), a serine protease that is expressed by a variety of cells, accumulates in the extracellular milieu during chronic inflammation and cleaves a number of ECM proteins. We hypothesized that GzmB contributes to ECM degradation in the skin after UV irradiation through both direct cleavage of ECM proteins and indirectly through the induction of other proteinases. Wild-type and GzmB-knockout mice were repeatedly exposed to minimal erythemal doses of solar-simulated UV irradiation for 20 weeks. GzmB expression was significantly increased in wild-type treated skin compared to nonirradiated controls, colocalizing to keratinocytes and to an increased mast cell population. 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 GzmB-mediated fibronectin fragments increased the expression of collagen-degrading matrix metalloproteinase-1 (MMP-1) in fibroblasts. Collectively, these findings indicate a significant role for GzmB in ECM degradation that may have implications in many age-related chronic inflammatory diseases.
authors.affiliation: Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Leigh G
authors.initials: LG
authors.lastname: Parkinson
authors.forename: Ana
authors.initials: A
authors.lastname: Toro
authors.forename: Hongyan
authors.initials: H
authors.lastname: Zhao
authors.forename: Keddie
authors.initials: K
authors.lastname: Brown
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Tebbutt
authors.forename: David J
authors.initials: DJ
authors.lastname: Granville
mesh_terms: D000818:Animals; D002452:Cell Count; D003094:Collagen / Q000378:metabolism; D058575:Decorin / Q000378:metabolism; D020405:Dermis / Q000473:pathology / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000201:enzymology / Q000528:radiation effects; D005353:Fibronectins / Q000378:metabolism; D053804:Granzymes / Q000172:deficiency / Q000378:metabolism*; D008407:Mast Cells / Q000201:enzymology / Q000528:radiation effects; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D021381:Protein Transport / Q000528:radiation effects; D059748:Proteolysis / Q000528:radiation effects; D012867:Skin / Q000378:metabolism* / Q000528:radiation effects*; D015595:Skin Aging / Q000528:radiation effects; D014466:Ultraviolet Rays
chemical_list: D058575:Decorin; D005353:Fibronectins; D003094:Collagen; D053804:Granzymes; D020781:Matrix Metalloproteinase 1
keywords: aging; collagen; extracellular matrix; fibronectin; granzyme B; matrix metalloproteinase; photoaging; skin; ultraviolet light