Biasing CXCR3 Signaling to Modulate the Inflammatory Response

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CXCR3 is a chemokine receptor (CKR) that plays a central role in inflammation through its regulation of T cell migration and function. Despite the established clinical relevance of CXCR3 in atherosclerosis, cancer metastasis and inflammatory bowel disease, there are no FDA-approved drugs that target this receptor. Indeed, there are only two FDA approved drugs that target the entire CKR family, which consists of twenty receptors that regulate nearly every aspect of inflammation. Reasons for the difficulty in drug development at CKRs include the potential redundancy between multiple cognate chemokine ligands for each CKR and a lack of knowledge regarding how they regulate immune cell function. Thus, despite their central role in a variety of disease states, there is a critical unmet need for drugs targeting CKRs. This puts into context recent results from my group in which we have discovered that the cognate ligands of CXCR3, CXCL9, 10 and 11, do not simply act as agonists or antagonists at the receptor, but generate both quantitatively and qualitatively distinct signals. This is a physiologically relevant example of “biased agonism”, a pharmacologic characteristic of G protein-coupled receptor (GPCR) signaling, in which different ligands for the same receptor induce distinct receptor conformations that impact their interaction with heterotrimeric G proteins or β-arrestin (βarr) adapter proteins, resulting in different biological outputs. Our findings suggest that it will be possible to exploit biased agonism at CXCR3 as a means to develop new classes of drugs that target disease-relevant signaling pathways while minimizing off-target effects. In our preliminary studies, we have identified small molecules that differentially activate G proteins and βarrs and generate distinct βarr conformations at CXCR3. It was also determined that these biased agonists (a) differentially activate kinases and transcriptional pathways; and (b) have distinct effects in a mouse model of inflammatory skin disease, findings that are consistent with the hypothesis that G proteins and βarrs differentially contribute to the CXCR3-mediated inflammatory response. The long-term goal of our research is to develop novel biased agonists targeting CKR signaling. The overall objective of the studies outlined in this application, therefore, is to identify the contributions of G protein- and βarr-mediated signaling to CXCR3-mediated inflammatory responses. Our central hypothesis is that these parallel pathways differentially contribute to the intracellular signaling pathways that regulate T cell function and inflammation. We plan to test our hypothesis and accomplish the objectives of this application by pursuing the following specific aims: (1) Use G protein- and βarr-biased CXCR3 endogenous and small molecule agonists to identify determinants of bias at CXCR3; (2) Identify signaling pathways regulated by βarrs and G proteins downstream of CXCR3; and (3) Determine how G protein- or βarr-mediated signaling underlies CXCR3-mediated inflammation. This project explores an innovative approach to target CXCR3 signaling to aid in the development of a novel class of molecules with significant therapeutic potential.