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Granzyme K: An Important Mediator of Cutaneous Inflammation and Re‐epithelialization
Author(s) -
Richardson Katlyn,
Turner Chris,
Zeglinski Matthew,
Zhao Hongyan,
Shen Yue,
Granville David
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.34.2
Subject(s) - inflammation , wound healing , fibrosis , medicine , granzyme , proinflammatory cytokine , immunology , pathology , dermis , cytokine , angiogenesis , granzyme a , immune system , granzyme b , t cell , cancer research , cd8 , perforin
Background Granzyme K (GzmK) is a serine protease traditionally thought as having a role in immune cell‐mediated killing. However, recent evidence has challenged this paradigm. We now believe GzmK is a mediator of inflammation. GzmK is elevated in plasma from patients with a variety of pro‐inflammatory disorders, including allergic asthma, endotoxemia, and sepsis. In addition, culture of endothelial cell, lung fibroblasts and activated macrophages with purified GzmK induces the secretion of pro‐inflammatory cytokines. In the present study we hypothesized that GzmK is elevated in cutaneous inflammation and contributes to impaired reepithelialization of cutaneous wounds. Methods GzmK expression was evaluated histologically in tissue from patients with a variety of inflammatory skin diseases and compared to healthy skin controls. Using a murine model of skin injury and repair, the role of GzmK was investigated. Wound severity was assessed macroscopically, comparing onset, severity and wound resolution between GzmK−/− and wildtype mice. Wound tissue was isolated and examined histologically, including wound morphometry (wound area, re‐epithelialization, epidermal thickness), GzmK expression, collagen organization (Masson's Trichrome, picosirius red, Collage I/III), inflammation (markers of T‐cells, macrophages, NK cells), angiogenesis (CD31) and fibrosis (α‐SMA). To further verify the role of GzmK in cutaneous inflammation, cultured keratinocytes and skin fibroblasts were exposed to GzmK and cytokine expression, cellular proliferation and viability were assessed. Results GzmK was markedly increased in biopsies from patients with skin wounds compared to normal skin, with negligible levels observed. Macrophages, namely classically activated M1, were identified as the predominant cell type responsible for GzmK expression and secretion. GzmK−/− mice exhibited expedited wound closure and wound maturation compared to equivalent wounds in wild‐type mice. Re‐epithelialization had the greatest disparity between GzmK−/− and wild‐type mice; vastly accelerated epithelialization observed in GzmK−/− mice suggests that keratinocytes may be particularly sensitive to GzmK insult. Additionally, in vitro cultured keratinocytes exhibited impaired wound healing, including decreased cell migration and viability, and an increase in pro‐inflammatory cytokines when exposed to GzmK. Conclusion GzmK is an important mediator of cutaneous inflammation and epithelialization; functioning to enhance the pro‐inflammatory phase of wound repair whilst simultaneously hindering re‐epithelialization. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .