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 March 10, 2020
Citation Information: J Clin Invest. 2020;130(6):3151-3157. https://doi.org/10.1172/JCI133159.
View: Text | PDF
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

×

Figure 3

Skin-directed Klk6 overexpression leads to debilitating joint inflammation and bony abnormalities consistent with psoriatic arthritis (PsA).

Options: View larger image (or click on image) Download as PowerPoint
Skin-directed Klk6 overexpression leads to debilitating joint inflammati...
(A) Gross images of control and Klk6+ transgenic forelimbs. (B) Curvature of control and Klk6+ spines visualized by micro-computed tomography (micro-CT). Data are representative of 6 animals per group. (C) Pelvic joints of control and Klk6+ mice visualized by micro-CT. Upper panels, sacroiliac (SI) joint; lower panels, pubic symphysis. Arrows, distortion of joint space in SI joints and bony erosions in pubic symphysis. Data are representative of 6 animals per group. SI joints are magnified in Figure 4B. (D) Vertebral body bone density as visualized by brightness (higher density) on micro-CT. (E) H&E staining of control and Klk6+ spine sections. Rightmost panel, misshapen vertebra at level of gross kyphosis. Data are representative of 3 animals. Scale bar: 100 μm. (F) H&E staining of Klk6+ paw sections showing synovial inflammation (black arrows) and enthesitis (white arrows). Arrowheads, bony erosions. Data are representative of 5 animals. Scale bar: 200 μm.