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Protease-activated Receptor 1 Plays a Proinflammatory Role in Colitis by Promoting Th17-related Immunity

Saeed, Muhammad A. PhD; Ng, Garrett Z. PhD; Däbritz, Jan MD; Wagner, Josef PhD; Judd, Louise PhD; Han, Jia-Xi BSc(Hons); Dhar, Poshmaal MSc; Kirkwood, Carl D. PhD; Sutton, Philip PhD

doi: 10.1097/MIB.0000000000001045
Original Basic Science Articles

Background: Proteolytic cleavage of protease-activated receptor 1 (PAR1) can result in potent downstream regulatory effects on inflammation. Although PAR1 is expressed throughout the gastrointestinal tract and activating proteases are increased in inflammatory bowel disease, the effect of PAR1 activation on colitis remains poorly understood, and has not previously been studied in pediatric disease.

Methods: Expression of PAR1 and inflammatory cytokines in colonic biopsies from pediatric patients with Crohn's disease exhibiting active moderate to severe colitis was measured by quantitative PCR. The functional relevance of these clinical data was further studied in a mouse model of Citrobacter rodentium–induced colitis.

Results: PAR1 expression was significantly upregulated in the inflamed colons of pediatric patients with Crohn's disease, with expression levels directly correlating to disease severity. In patients with severe colitis, PAR1 expression uniquely correlated with Th17-related (IL17A, IL22, and IL23A) cytokines. Infection of PAR1-deficient (PAR1−/−) and wildtype mice with colitogenic C. rodentium revealed that disease severity and colonic pathology were strongly attenuated in mice lacking PAR1. Furthermore, Th17-type immune response was completely abolished in the colons of infected PAR1−/− but not wildtype mice. Finally, PAR1 was shown to be essential for secretion of the Th17-driving cytokine IL-23 by C. rodentium–stimulated macrophages.

Conclusions: This study demonstrates a strong link between PAR1 expression, Th17-type immunity, and disease severity in both pediatric patients with Crohn's disease and C. rodentium–induced colitis in mice. The data presented suggest PAR1 exerts a proinflammatory role in colitis in both humans and mice by promoting a Th17-type immune response, potentially by supporting the production of IL-23.

Published online 28 February 2017

*Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Melbourne, Victoria, Australia;

Centre for Animal Biotechnology, Faculty of Veterinary and Agricultural Science, University of Melbourne, Melbourne, Victoria, Australia;

Department of Paediatrics, University Medicine Rostock, Rostock, Mecklenburg-Vorpommern, Germany; and

§Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia.

Address correspondence to: Philip Sutton, PhD, Mucosal Immunology, Murdoch Childrens Research Institute, Royal Children's Hospital, Flemington Road, Parkville, Melbourne, Victoria 3052, Australia (e-mail: phil.sutton@mcri.edu.au).

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.ibdjournal.org).

This work was partly supported by the Victorian Government's Operational Infrastructure Support Program. M. A. Saeed was supported by a scholarship from the University of Melbourne. P. Sutton was supported by a Senior Research Fellowship from the National Health and Medical Research Council of Australia.

The authors have no conflict of interest to disclose.

Received October 21, 2016

Accepted January 02, 2017

© Crohn's & Colitis Foundation of America, Inc.
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