@article{c751f633ed784801978f9b6bd238eae9,
title = "KLK6 expression in skin induces PAR1-mediated psoriasiform dermatitis and inflammatory joint disease",
abstract = "Kallikrein-related peptidase 6 (KLK6) is a secreted serine protease hypothesized to promote inflammation via cleavage of protease-activated receptor 1 (PAR1) 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 arthritislike 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 patients with psoriasis. 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.",
author = "Billi, {Allison C.} and Ludwig, {Jessica E.} and Yi Fritz and Richard Rozic and Swindell, {William R.} and Tsoi, {Lam C.} and Dennis Gruzska and Shahla Abdollahi-Roodsaz and Xianying Xing and Doina Diaconu and Ranjitha Uppala and Camhi, {Maya I.} and Klenotic, {Philip A.} and Sarkar, {Mrinal K.} and Husni, {M. Elaine} and Scher, {Jose U.} and Christine McDonald and Kahlenberg, {J. Michelle} and Midura, {Ronald J.} and Gudjonsson, {Johann E.} and Ward, {Nicole L.}",
note = "Funding Information: This work was supported by the Lozick Discovery Grant and a Bridge Grant from the National Psoriasis Foundation (to NLW), the Babcock Endowment Fund (to JEG), the A. Alfred Taubman Medical Research Institute (to JEG), NIH awards R01-AR069071 and R01-AR073196 (to JEG and NLW); P30-AR075043, R01-AI130025 (to JEG); P30-AR39750, P50-AR055508, P50-AR070590, R01-AR063437, R01-AR062546, and R21-AR063852 (to NLW); T32-AR007197 (to ACB), and a core utilization grant from the Clinical and Translational Science Collaborative of Cleveland (4UL1TR0002548), from the National Center for Advancing Translational Sciences (NCATS) component of the NIH and NIH Roadmap for Medical Research. The contents of this paper are the responsibility of the authors and do not necessarily represent the official views of the NIH. Publisher Copyright: {\textcopyright} 2020, American Society for Clinical Investigation.",
year = "2020",
month = jun,
day = "1",
doi = "10.1172/JCI133159",
language = "English (US)",
volume = "130",
pages = "3151--3157",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "6",
}