KLK6 expression in skin induces PAR1-mediated psoriasiform dermatitis and inflammatory joint disease
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
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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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 2

Epidermal Klk6 overexpression causes a severe, generalized skin rash with histologic, transcriptional, and immunological features of psoriasis.

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Epidermal Klk6 overexpression causes a severe, generalized skin rash wit...
(A) Gross images of age- and sex-matched control and Klk6+ transgenic mice. (B) H&E staining of control (N = 19) and Klk6+ (N = 38) dorsal skin. (C) Immunostaining in control and Klk6+ dorsal skin. Ki67, cell proliferation; CD4 and CD8a, T lymphocyte; GR1, granulocyte (including neutrophil); CD11c, dendritic cell; F4/80, macrophage; MECA, vascular endothelial cell. (D) Detection of IL-17A, the IL-12/23p40 subunit, the IL-23p19 subunit, and IL-6 by ELISA in control and Klk6+ skin. N ≥ 7 for all groups. P = 0.0027, P < 0.0001, P = 0.0056, and P = 0.0015, respectively, by Mann-Whitney test. Mean and SEM are indicated. (E) Phospho-STAT3 (p-STAT3) immunostaining of control and Klk6+ dorsal skin. (F) Blue-yellow heatmap showing relative expression of transcripts enriched (top panel) and depleted (bottom panel) in Klk6+ (N = 5) vs. control (N = 5) dorsal skin. Adjacent blue-red heatmaps show fold change (FC) estimates from the following 3 comparisons: Klk6+ vs. control mice, psoriatic lesional (PP) vs. nonlesional (PN) skin, and lesional skin from psoriatic arthritis patients (PsA) vs. cutaneous-only psoriatic patients (PsC). Significance by P value or false discovery rate (FDR) is indicated by solid or open arrowheads, respectively. Panels depict the 25 transcripts with the highest minimum (top) or lowest maximum (bottom) FC estimates across the 3 comparisons. For additional details, see Supplemental Methods. Scale bars: 100 μm (B, C, and E).