KLK6 expression in skin induces PAR1-mediated psoriasiform dermatitis and inflammatory joint disease
Allison C. Billi, … , Johann E. Gudjonsson, Nicole L. Ward
Allison C. Billi, … , Johann E. Gudjonsson, Nicole L. Ward
Published June 1, 2020; First published March 10, 2020
Citation Information: J Clin Invest. 2020;130(6):3151-3157. https://doi.org/10.1172/JCI133159.
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Concise Communication Dermatology Inflammation

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 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 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.

Authors

Allison C. Billi, Jessica E. Ludwig, Yi Fritz, Richard Rozic, William R. Swindell, Lam C. Tsoi, Dennis Gruzska, Shahla Abdollahi-Roodsaz, Xianying Xing, Doina Diaconu, Ranjitha Uppala, Maya I. Camhi, Philip A. Klenotic, Mrinal K. Sarkar, M. Elaine Husni, Jose U. Scher, Christine McDonald, J. Michelle Kahlenberg, Ronald J. Midura, Johann E. Gudjonsson, Nicole L. Ward

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Figure 1

KLK6 expression is significantly elevated in psoriatic lesions and parallels disease activity.

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KLK6 expression is significantly elevated in psoriatic lesions and paral...
(A) Detection of KLK transcripts by RNA-seq in healthy control skin (NN, gray; N = 90), psoriatic patient nonlesional skin (PN, yellow; N = 26), and psoriatic patient lesional skin (PP, blue; N = 99). P values were computed using Wilcoxon’s rank-sum test; false discovery rate (FDR) was used to control the multiple testing. *P < 0.05 in PP vs. PN. (B) Relative expression of select KLK transcripts by qRT-PCR in a unique cohort of healthy controls and psoriatic patients (N ≥ 6 for all). Mean is indicated by the horizontal line. Box, 25th–75th percentile. Whiskers, minimum and maximum. *P < 0.005 in PP vs. both NN and PN by ordinary 1-way ANOVA with post hoc Tukey’s multiple-comparisons test. (C) Immunostaining of KLK6 in human skin. Results are representative of 4 biological replicates. Scale bar: 100 μm. (D) Detection of KLK6 and S100A7 transcripts by RNA-seq in PN and PP at the indicated weeks’ duration of etanercept therapy in responsive patients (N = 14). Mean is indicated by the horizontal line. Box, 25th–75th percentile. For definition of whiskers and additional details, see Supplemental Methods. *P < 0.05 vs. PN at w0; +P < 0.05 vs. PP at w0 by negative binomial test.