KLK6 expression in skin induces PAR1-mediated psoriasiform dermatitis and inflammatory joint disease
Open Access
- 1 June 2020
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 130 (6), 3151-3157
- https://doi.org/10.1172/jci133159
Abstract
Kallikrein-related peptidase 6 (KLK6) is a secreted serine protease hypothesized to promote inflammation via cleavage of protease-activated receptors (PAR)1 and PAR2. KLK6 levels are elevated in multiple inflammatory and autoimmune conditions, but no definitive role in pathogenesis has been established. Here, we show that skin-targeted overexpression of KLK6 causes generalized, severe psoriasiform dermatitis with spontaneous development of debilitating psoriatic arthritis-like joint disease. The psoriatic skin and joint phenotypes are reversed by normalization of skin KLK6 levels and attenuated following genetic elimination of PAR1 but not PAR2. Conservation of this regulatory pathway was confirmed in human psoriasis using vorapaxar, an FDA-approved PAR1 antagonist, on explanted lesional skin from psoriasis patients. Beyond defining a critical role for KLK6-PAR1 signaling in promoting psoriasis, our results demonstrate that KLK6-PAR1-mediated inflammation in the skin alone is sufficient to drive inflammatory joint disease. Further, we identify PAR1 as a promising cytokine-independent target in therapy of psoriasis and psoriatic arthritis.Funding Information
- National Psoriasis Foundation (Lozick Discovery Grant,Bridge Grant)
- Babcock Endowment Fund (N/A)
- A. Alfred Taubman Medical Research Institute (N/A)
- National Institutes of Health (R01-AR069071,R01-AR073196,P30-AR075043,R01-AI130025,P30-AR39750,P50-AR055508,P50-AR070590,R01-AR063437,R01-AR062546,R21-AR063852,T32AR007197-41,4UL1TR0002548)
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