KLK6 expression in skin induces PAR1-mediated psoriasiform dermatitis and inflammatory joint disease.

The Journal of Clinical Investigation
Allison C BilliNicole L Ward

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.

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Citations

Apr 2, 2020·Nature Reviews. Rheumatology·Joanna Clarke
Jun 21, 2020·The Journal of Allergy and Clinical Immunology·Michael P SchönLuise Erpenbeck
Jun 14, 2020·The Journal of Investigative Dermatology·Piotr Konieczny, Shruti Naik
Feb 6, 2021·Experimental Dermatology·Georgia SotiropoulouGeorgios Pampalakis
Oct 16, 2020·JCI Insight·Yanyun JiangJohann E Gudjonsson
Aug 9, 2021·The Journal of Investigative Dermatology·Mehrnaz Gharaee-KermaniJ Michelle Kahlenberg

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Datasets Mentioned

BETA
GSE144312

Methods Mentioned

BETA
transgenic
RNA-seq

Related Concepts

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