Granzyme K contributes to endothelial microvascular damage and leakage during skin inflammation
Date
2023
Authors
Turner, C.T.
Zeglinski, M.R.
Boivin, W.
Zhao, H.
Pawluk, M.A.
Richardson, K.C.
Chandrabalan, A.
Bird, P.
Ramachandran, R.
Sehmi, R.
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Journal article
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British Journal of Dermatology, 2023; 189(3):279-291
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Abstract
<h4>Background</h4>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.<h4>Objectives</h4>To evaluate the role of GzmK in the pathogenesis of atopic dermatitis (AD), the most common inflammatory skin disease.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>GzmK may provide a potential therapeutic target for skin conditions associated with persistent inflammation, vasculitis and pathological angiogenesis.
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Copyright 2022 The author(s), published by Oxford University Press.