FC18 Par1 signalling between T cells and keratinocytes mediates Klk6-elicited skin inflammation in a ROCK2-independent manner

Abstract Kallikrein 6 (KLK6) is highly elevated in lesional epidermis of human psoriasis, and keratinocyte (K5)-specific overexpression of Klk6 (Klk6+) in mice results in the spontaneous development of psoriasis-like skin lesions that are abrogated in the global absence of the protease-activated receptor (Par)1. PAR1, a G-protein coupled receptor, is expressed on keratinocytes (KCs) and T cells and can signal via phosphorylation of ROCK2. We tested the hypothesis that Klk6-Par1 signalling via ROCK2 drives the development of psoriasiform skin inflammation in Klk6+ mice and sought to identify whether KCs and/or T cells were pathogenically responsible. Klk6+ mice have increases in cutaneous ROCK2 activity compared with littermate controls that significantly decreases in the absence of Par1. However, following 4 weeks of systemic interference with ROCK2 signalling in Klk6+ mice, no improvement in skin inflammation was observed, despite ROCK2 activity levels decreasing to control mouse levels, indicating that the skin phenotype occurred in a ROCK2-independent manner. Next, we sought to identify whether Par1 on KCs or T cells was critical for the development of Klk6+ skin inflammation. Klk6+ mice were mated with KC (K14cre) or T-cell (Lckcre)-specific Par1 knockout mice (Parfl/ex). Both Klk6+-Par1ΔKC and Klk6+Par1ΔTcell mice developed significantly less severe skin inflammation than Klk6+ mice, demonstrated by overall improvement in appearance, significantly decreased acanthosis, and decreases in cutaneous T cells. Klk6-Par1 signalling in primary mouse T cells led to increases in Il17a and Ifng that retained their capacity to interact and elicit inflammatory signals from the KC, which was disrupted in T cells deficient in Par1. Together, these findings suggest that Klk6-Par1 signalling between T cells and keratinocytes is critical for skin inflammation and this occurs in a ROCK2-independent manner. These data provide new pathogenic insight into the cellular mechanisms underlying Klk6-Par1-mediated skin inflammation.