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- Title
Granzyme K contributes to endothelial microvascular damage and leakage during skin inflammation.
- Authors
Turner, Christopher T; Zeglinski, Matthew R; Boivin, Wendy; Zhao, Hongyan; Pawluk, Megan A; Richardson, Katlyn C; Chandrabalan, Arundhasa; Bird, Phillip; Ramachandran, Rithwik; Sehmi, Roma; Lima, Hermenio; Gauvreau, Gail; Granville, David J
- Abstract
Background Granzyme K (GzmK) is a serine protease with minimal presence in healthy tissues while abundant in inflamed tissues. Initially thought to play an exclusive role in immune-mediated cell death, extracellular GzmK can also promote inflammation. Objectives To evaluate the role of GzmK in the pathogenesis of atopic dermatitis (AD), the most common inflammatory skin disease. Methods A panel of human AD and control samples was analysed to determine if GzmK is elevated. Next, to determine a pathological role for GzmK in AD-like skin inflammation, oxazolone-induced dermatitis was induced in GzmK− / − and wild-type (WT) mice. Results In human lesional AD samples, there was an increase in the number of GzmK+ cells compared with healthy controls. GzmK− / − mice exhibited reduced overall disease severity characterized by reductions in scaling, erosions and erythema. Surprisingly, the presence of GzmK did not notably increase the overall pro-inflammatory response or epidermal barrier permeability in WT mice; rather, GzmK impaired angiogenesis, increased microvascular damage and microhaemorrhage. Mechanistically, GzmK contributed to vessel damage through cleavage of syndecan-1, a key structural component of the glycocalyx, which coats the luminal surface of vascular endothelia. Conclusions GzmK may provide a potential therapeutic target for skin conditions associated with persistent inflammation, vasculitis and pathological angiogenesis.
- Subjects
SKIN inflammation; GRANZYMES; LEAKAGE; ATOPIC dermatitis; SKIN diseases
- Publication
British Journal of Dermatology, 2023, Vol 189, Issue 3, p279
- ISSN
0007-0963
- Publication type
Article
- DOI
10.1093/bjd/ljac017