Granzyme B Contributes to Barrier Dysfunction in Oxazolone-Induced Skin Inflammation through E-Cadherin and FLG Cleavage

Christopher T. Turner, Matthew R. Zeglinski, Katlyn C. Richardson, Stephanie Santacruz, Sho Hiroyasu, Christine Wang, Hongyan Zhao, Yue Shen, Roma Sehmi, Hermenio Lima, Gail M. Gauvreau, David J. Granville

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26 Citations (Scopus)

Abstract

Atopic dermatitis (AD) is the most common inflammatory skin condition. Skin barrier dysfunction is of major importance in AD because it facilitates allergen sensitization and systemic allergic responses. Long regarded as a pro-apoptotic protease, emerging studies indicate granzyme B (GzmB) to have extracellular roles involving the proteolytic cleavage of extracellular matrix, cell adhesion proteins, and basement membrane proteins. Minimally expressed in normal skin, GzmB is elevated in AD and is positively correlated with disease severity and pruritus. We hypothesized that GzmB contributes to AD through extracellular protein cleavage. A causative role for GzmB was assessed in an oxazolone-induced murine model of dermatitis, comparing GzmB−/− mice with wild-type mice, showing significant reductions in inflammation, epidermal thickness, and lesion formation in GzmB−/− mice. Topical administration of a small-molecule GzmB inhibitor reduced disease severity compared with vehicle-treated controls. Mechanistically, GzmB impaired epithelial barrier function through E-cadherin and FLG cleavage. GzmB proteolytic activity contributes to impaired epidermal barrier function and represents a valid therapeutic target for AD.

Original languageEnglish
Pages (from-to)36-47
Number of pages12
JournalJournal of Investigative Dermatology
Volume141
Issue number1
DOIs
Publication statusPublished - Jan 2021
Externally publishedYes

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