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Granzyme K contributes to endothelial microvascular damage and leakage during skin inflammation

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dc.contributor.authorTurner, C.T.
dc.contributor.authorZeglinski, M.R.
dc.contributor.authorBoivin, W.
dc.contributor.authorZhao, H.
dc.contributor.authorPawluk, M.A.
dc.contributor.authorRichardson, K.C.
dc.contributor.authorChandrabalan, A.
dc.contributor.authorBird, P.
dc.contributor.authorRamachandran, R.
dc.contributor.authorSehmi, R.
dc.contributor.authorLima, H.
dc.contributor.authorGauvreau, G.
dc.contributor.authorGranville, D.J.
dc.date.issued2023
dc.description.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.
dc.identifier.citationBritish Journal of Dermatology, 2023; 189(3):279-291
dc.identifier.doi10.1093/bjd/ljac017
dc.identifier.issn0007-0963
dc.identifier.issn1365-2133
dc.identifier.orcidTurner, C.T. [0000-0001-7409-4386]
dc.identifier.urihttps://hdl.handle.net/11541.2/33087
dc.language.isoen
dc.publisherOXFORD UNIV PRESS
dc.rightsCopyright 2022 The author(s), published by Oxford University Press.
dc.source.urihttps://doi.org/10.1093/bjd/ljac017
dc.subjectEpidermis
dc.subjectSkin
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectDermatitis, Atopic
dc.subjectInflammation
dc.subjectGranzymes
dc.titleGranzyme K contributes to endothelial microvascular damage and leakage during skin inflammation
dc.typeJournal article
pubs.publication-statusPublished
ror.mmsid9916721816901831

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