CRTH2 is Critical to the Development of Colitis Induced by Dextran Sodium Sulfate (DSS)

Abstract

Chemoattractant Receptor-homologous molecule expressed on Th2 cells [CRTH2] is expressed on granulocytes (eosinophils, basophils and neutrophils), Th2 cells and monocytes. CRTH2 has been implicated in the development of cutaneous inflammation as CRTH2 + CD4 + T cells and CRTH2 + eosinophils are increased in the blood of atopic dermatitis patients. CRTH2 is also up-regulated in circulating neutrophils of psoriatic patients. Interestingly, CRTH2 is detected in the mucosa of patients with Inflammatory Bowel Disease (IBD) ulcerative colitis, where the CRTH2 positive cells localize within and adjacent to regions of inflamed mucosa suggesting that CRTH2 may play a role in IBD. However, the exact downstream inflammatory pathways resulting from CRTH2 activation in colitis are not well characterized. To gain a better understanding of the effects of CRTH2 activation in the pathogenesis of colitis, we have generated a small molecule inhibitor against CRTH2 and its potency was first validated in an oxazolone induced contact dermatitis model. We investigated the consequences of inhibiting CRTH2 in the development of IBD using a Dextran Sodium Sulfate (DSS)-induced colitis mouse model. Compared to the vehicle control group, mice treated with a selective CRTH2 antagonist had reduced disease severity as measured by weight loss, as well as serum acute phase protein, haptoglobin. Furthermore, pro-inflammatory cytokine gene expression for TNFα, IL-1β, IL-6, IL-17A, and IFNγ were reduced in colons of mice that had been treated with the CRTH2 antagonist compared with DSS treated controls that received vehicle. Taken together, our data identify a previously unrecognized role for CRTH2 in the initiation/amplification and/or stabilization of colon inflammation.