炎症
血管生成
颗粒酶A
免疫学
发病机制
医学
血管通透性
颗粒酶
红斑
病理
免疫系统
颗粒酶B
T细胞
CD8型
癌症研究
穿孔素
作者
Cathy Turner,Matthew R. Zeglinski,Wendy A. Boivin,Hongyan Zhao,Megan A Pawluk,Katlyn C. Richardson,Arundhasa Chandrabalan,Phillip I. Bird,Rithwik Ramachandran,Roma Sehmi,Hermenio Lima,Gail Gauvreau,David J. Granville
摘要
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.
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