CXCR3 Axis: Role in Inflammatory Bowel Disease and its Therapeutic Implication

Udai   P.   Singh; Chandrasekar      Venkataraman; Rajesh      Singh; James   W.   Lillard Jr.

doi:10.2174/187153007780832109

Abstract

There is a great need for new intervention and prevention strategies against Crohns disease (CD), a chronic, relapsing tissue-destructive inflammatory bowel disease (IBD). Estimates indicate more than 1 million cases of IBD in the United States occur annually, with 50% involving CD. The clinical features of CD correlate with certain mouse models of colitis, including the spontaneous colitis observed in interleukin-10 deficient (IL-10-/-), senescence accelerated mice (SAMP1/Yit) and trinitrobenzene sulfonic acid (TNBS)-treated mice. Chemokines undoubtedly play a pivotal role in the regulation (i.e., initiation, maintenance, and suppression) of mucosal inflammation and tissue destruction. A number of key advances have led to greater understanding of the steps responsible for colitis and the roles played by chemokines. In fact, CXCR3 and the ligands for this chemokine receptor, monokine-induced by interferon-γ (IFN-γ) (MIG/CXCL9), IFN- γ-inducible 10 kDa protein (IP-10/CXCL10), and IFN-γ-inducible T cell α-chemoattractant (I-TAC/CXCL11) are differentially expressed at sites of colitis in IL-10-/- mice and in clinical cases of CD. While we have demonstrated that antibodies directed against CXCL10 could both prevent the onset and cure of pre-existing colitis in IL-10-/- mice, studies by other investigators have shown the efficacy of CXCR3 blockade to mitigate colitis and other inflammatory diseases. This review describes the hallmarks of IBD, CXCL9-11, and CXCR3 expression during murine colitis and IBD, gives an overview of the antagonist therapies targeting the CXCR3 axis, details current and pending bio-therapies for IBD, and discusses what is known about the cellular and CXCR3-mediated mechanisms of colitis.

Keywords: Crohn's disease, Senescence-accelerated mice, T cell responses, CXCR3 ligands, chemokines, Colitis