Background and aims: The role of protease-activated receptor-2 (PAR2) during intestinal inflammation is still unclear due to the fact that PAR2-activating peptide has both pro- and anti-inflammatory properties. The aim of this study was to investigate the effects of PAR2 deficiency (using PAR2-deficient mice, PAR2−/−) in models of colitis, in order to elucidate the role of endogenous PAR2 in the process of inflammation in the gut.
Methods: Colonic inflammation in wild-type and PAR2−/− mice was induced by dextran sodium sulfate, trinitrobenzene sulfonic acid (TNBS), a T helper-1 predominant model, or oxazolone, a T helper-2 predominant model. Leukocyte recruitment, assessed by intravital microscopy, and inflammatory parameters (myeloperoxidase (MPO), macroscopic and microscopic damage) were assessed during the development of colitis. Lastly, the protein levels of cyclooxygenases (COXs) and adhesion molecules (ICAM-1, VCAM-1, alpha-M, alpha-4) were assessed by using western blot analysis.
Results: In all three models of colitis, MPO activity, macroscopic damage score and bowel thickness were significantly lower in PAR2−/− mice. Changes in vessel leukocyte recruitment parameters (rolling and adhesion) were also significantly reduced in PAR2−/− mice compared to wild-type mice after the induction of colitis. The protein expression of ICAM-1, VCAM-1 and alpha-4 was significantly attenuated, whereas the expression of COX-1 was significantly increased in PAR2−/− mice challenged with TNBS-induced colitis.
Conclusions: The role of endogenous PAR2 in the gut is pro-inflammatory and independent of the T helper-1 or -2 cytokine profile. Endogenous PAR2 activation controls leukocyte recruitment in the colon and thus appears as a new potential therapeutic target for the treatment of inflammatory bowel disease.
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Funding: This work was supported by the Crohn’s and Colitis Foundation of Canada, the Canadian Institute of Health Research, the Fondation Bettencourt-Schueller, and the INSERM-AVENIR program (to NV).
Competing interests: None.
Ethics approval: The Animal Care and Ethic Committees of the University of Calgary approved all experimental protocols, which followed the guidelines of the Canadian Council on Animal Care, 2006.