The role of CXCR3 in DSS-induced colitis.

Belal Chami,Amanda W. S. Yeung,Caryn van Vreden,Shisan Bao,Nicholas J. C. King,Rasheed Ahmad

doi:10.1371/journal.pone.0101622

Belal Chami, Amanda W. S. Yeung + Show 4 more

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https://doi.org/10.1371/journal.pone.0101622

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Abstract

Inflammatory bowel disease (IBD) is a group of disorders that are characterized by chronic, uncontrolled inflammation in the intestinal mucosa. Although the aetiopathogenesis is poorly understood, it is widely believed that IBD stems from a dysregulated immune response towards otherwise harmless commensal bacteria. Chemokines induce and enhance inflammation through their involvement in cellular trafficking. Reducing or limiting the influx of these proinflammatory cells has previously been demonstrated to attenuate inflammation. CXCR3, a chemokine receptor in the CXC family that binds to CXCL9, CXCL10 and CXCL11, is strongly overexpressed in the intestinal mucosa of IBD patients. We hypothesised that CXCR3 KO mice would have impaired cellular trafficking, thereby reducing the inflammatory insult by proinflammatory cell and attenuating the course of colitis. To investigate the role of CXCR3 in the progression of colitis, the development of dextran sulfate sodium (DSS)-induced colitis was investigated in CXCR3−/− mice over 9 days. This study demonstrated attenuated DSS-induced colitis in CXCR3−/− mice at both the macroscopic and microscopic level. Reduced colitis correlated with lower recruitment of neutrophils (p = 0.0018), as well as decreased production of IL-6 (p<0.0001), TNF (p = 0.0038), and IFN-γ (p = 0.0478). Overall, our results suggest that CXCR3 plays an important role in recruiting proinflammatory cells to the colon during colitis and that CXCR3 may be a therapeutic target to reduce the influx of proinflammatory cells in the inflamed colon.

Highlights

Inflammatory bowel disease (IBD) is characterized by chronic, uncontrolled inflammation in the intestinal mucosa, affecting millions of people worldwide, with a corresponding economic burden [1,2,3,4]
A previous study has reported attenuated DSS-induced colitis by simultaneous blockage of chemokine receptors CCR2, CCR5 and CXCR3 [27], we demonstrate that CXCR3-deficient (KO) mice alone challenged with dextran sulfate sodium (DSS) are resistant to the development of experimental colitis
DSS-induced colitis model To examine the role of CXCR3 in the induction and development of colitis, wild type (Wt) and KO mice were challenged with 2.5% DSS administered via the drinking water for 9 days

Summary

Introduction

Inflammatory bowel disease (IBD) is characterized by chronic, uncontrolled inflammation in the intestinal mucosa, affecting millions of people worldwide, with a corresponding economic burden [1,2,3,4]. DSS is thought to permeablise the mucosal membrane of the colon to enteric bacterial [6] by inducing epithelial injury [7]. Given the destructive nature of cellular infiltrates in the intestinal mucosa during IBD [9,10], many studies have focused on the importance of recruitment factors, such as chemokines, in the development of the disease. CXCR3, a chemokine receptor in the CXC family, has been implicated in the pathogenesis of several chronic diseases including rheumatoid arthritis [11], multiple sclerosis [12], dry eye syndrome [13], and psoriasis [14]. Epithelial and endothelial cells, as well as a wide range of lymphoid cells such as memory T cells, NK cells, B cells, neutrophils and monocytes, express CXCR3 [11,18,19,20,21]

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