AUTHOR=Richardson Katlyn C. , Aubert Alexandre , Turner Christopher T. , Nabai Layla , Hiroyasu Sho , Pawluk Megan A. , Cederberg Rachel A. , Zhao Hongyan , Jung Karen , Burleigh Angela , Crawford Richard I. , Granville David J. 

TITLE=Granzyme K mediates IL-23-dependent inflammation and keratinocyte proliferation in psoriasis

JOURNAL=Frontiers in Immunology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1398120

DOI=10.3389/fimmu.2024.1398120

ISSN=1664-3224

ABSTRACT=<p>Psoriasis is an inflammatory disease with systemic manifestations that most commonly presents as itchy, erythematous, scaly plaques on extensor surfaces. Activation of the IL-23/IL-17 pro-inflammatory signaling pathway is a hallmark of psoriasis and its inhibition is key to clinical management. Granzyme K (GzmK) is an immune cell-secreted serine protease elevated in inflammatory and proliferative skin conditions. In the present study, human psoriasis lesions exhibited elevated GzmK levels compared to non-lesional psoriasis and healthy control skin. In an established murine model of imiquimod (IMQ)-induced psoriasis, genetic loss of GzmK significantly reduced disease severity, as determined by delayed plaque formation, decreased erythema and desquamation, reduced epidermal thickness, and inflammatory infiltrate. Molecular characterization <italic>in vitro</italic> revealed that GzmK contributed to macrophage secretion of IL-23 as well as PAR-1-dependent keratinocyte proliferation. These findings demonstrate that GzmK enhances IL-23-driven inflammation as well as keratinocyte proliferation to exacerbate psoriasis severity.</p>