CXCR3

CXCR3 is expressed primarily on activated T lymphocytes and NK cells,{{cite journal | vauthors = Qin S, Rottman JB, Myers P, Kassam N, Weinblatt M, Loetscher M, Koch AE, Moser B, Mackay CR | title = The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions | journal = The Journal of Clinical Investigation | volume = 101 | issue = 4 | pages = 746–754 | date = February 1998 | pmid = 9466968 | pmc = 508621 | doi = 10.1172/JCI1422 }} and some epithelial cells. CXCR3 and CCR5 are preferentially expressed on Th1 cells, whereas Th2 cells favor the expression of CCR3 and CCR4. CXCR3 ligands that attract Th1 cells can concomitantly block the migration of Th2 cells in response to CCR3 ligands, thus enhancing the polarization of effector T cell recruitment.

Binding of CXCL9, CXCL10, and CXCL11 to CXCR3 is able to elicit increases in intracellular Ca²⁺⁺ levels and activate phosphoinositide 3-kinase and mitogen-activated protein kinase (MAPK).{{cite journal | vauthors = Smit MJ, Verdijk P, van der Raaij-Helmer EM, Navis M, Hensbergen PJ, Leurs R, Tensen CP | title = CXCR3-mediated chemotaxis of human T cells is regulated by a Gi- and phospholipase C-dependent pathway and not via activation of MEK/p44/p42 MAPK nor Akt/PI-3 kinase | journal = Blood | volume = 102 | issue = 6 | pages = 1959–1965 | date = September 2003 | pmid = 12750173 | doi = 10.1182/blood-2002-12-3945 | doi-access = free }} Detailed signaling pathway has not yet been established, but may include the same enzymes that were identified in the signaling cascade induced by other chemokine receptors.

CXCR3 is able to regulate leukocyte trafficking. Binding of chemokines to CXCR3 induces various cellular responses, most notably integrin activation, cytoskeletal changes and chemotactic migration. CXCR3-ligand interaction attracts Th1 cells and promotes Th1 cell maturation.

As a consequence of chemokine-induced cellular desensitization (phosphorylation-dependent receptor internalization), cellular responses are typically rapid and short in duration. Cellular responsiveness is restored after dephosphorylation of intracellular receptors and subsequent recycling to the cell surface. A hallmark of CXCR3 is its prominent expression in in vitro cultured effector/memory T cells, and in T cells present in many types of inflamed tissues. In addition, CXCL9, CXCL10 and CXCL11 are commonly produced by local cells in inflammatory lesion, suggesting that CXCR3 and its chemokines participate in the recruitment of inflammatory cells.{{cite web | title = Entrez Gene: CXCR3 chemokine (C-X-C motif) receptor 3| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2833}} Additionally, CXCR3 has been implicated in wound healing.{{cite journal | vauthors = Yates CC, Whaley D, Kulasekeran P, Hancock WW, Lu B, Bodnar R, Newsome J, Hebda PA, Wells A | title = Delayed and deficient dermal maturation in mice lacking the CXCR3 ELR-negative CXC chemokine receptor | journal = The American Journal of Pathology | volume = 171 | issue = 2 | pages = 484–495 | date = August 2007 | pmid = 17600132 | pmc = 1934531 | doi = 10.2353/ajpath.2007.061092 }}

CXCR3 has been implicated in the following diseases atherosclerosis,{{cite journal | vauthors = Mach F, Sauty A, Iarossi AS, Sukhova GK, Neote K, Libby P, Luster AD | title = Differential expression of three T lymphocyte-activating CXC chemokines by human atheroma-associated cells | journal = The Journal of Clinical Investigation | volume = 104 | issue = 8 | pages = 1041–1050 | date = October 1999 | pmid = 10525042 | pmc = 408576 | doi = 10.1172/JCI6993 }} multiple sclerosis,{{cite journal | vauthors = Sørensen TL, Tani M, Jensen J, Pierce V, Lucchinetti C, Folcik VA, Qin S, Rottman J, Sellebjerg F, Strieter RM, Frederiksen JL, Ransohoff RM | title = Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients | journal = The Journal of Clinical Investigation | volume = 103 | issue = 6 | pages = 807–815 | date = March 1999 | pmid = 10079101 | pmc = 408141 | doi = 10.1172/JCI5150 }} pulmonary fibrosis,{{cite journal | vauthors = Jiang D, Liang J, Hodge J, Lu B, Zhu Z, Yu S, Fan J, Gao Y, Yin Z, Homer R, Gerard C, Noble PW | title = Regulation of pulmonary fibrosis by chemokine receptor CXCR3 | journal = The Journal of Clinical Investigation | volume = 114 | issue = 2 | pages = 291–299 | date = July 2004 | pmid = 15254596 | pmc = 449741 | doi = 10.1172/JCI16861 }} type 1 diabetes,{{cite journal | vauthors = Frigerio S, Junt T, Lu B, Gerard C, Zumsteg U, Holländer GA, Piali L | title = Beta cells are responsible for CXCR3-mediated T-cell infiltration in insulitis | journal = Nature Medicine | volume = 8 | issue = 12 | pages = 1414–1420 | date = December 2002 | pmid = 12415259 | doi = 10.1038/nm792 }} autoimmune myasthenia gravis, nephrotoxic nephritis,{{cite journal | vauthors = Panzer U, Steinmetz OM, Paust HJ, Meyer-Schwesinger C, Peters A, Turner JE, Zahner G, Heymann F, Kurts C, Hopfer H, Helmchen U, Haag F, Schneider A, Stahl RA | title = Chemokine receptor CXCR3 mediates T cell recruitment and tissue injury in nephrotoxic nephritis in mice | journal = Journal of the American Society of Nephrology | volume = 18 | issue = 7 | pages = 2071–2084 | date = July 2007 | pmid = 17538187 | doi = 10.1681/ASN.2006111237 | doi-access = free }} acute cardiac allograft rejection,{{cite journal | vauthors = Hancock WW, Lu B, Gao W, Csizmadia V, Faia K, King JA, Smiley ST, Ling M, Gerard NP, Gerard C | title = Requirement of the chemokine receptor CXCR3 for acute allograft rejection | journal = The Journal of Experimental Medicine | volume = 192 | issue = 10 | pages = 1515–1520 | date = November 2000 | pmid = 11085753 | pmc = 2193193 | doi = 10.1084/jem.192.10.1515 }} allergic contact dermatitis,{{cite journal | vauthors = Smith JS, Nicholson LT, Suwanpradid J, Glenn RA, Knape NM, Alagesan P, Gundry JN, Wehrman TS, Atwater AR, Gunn MD, MacLeod AS, Rajagopal S | title = Biased agonists of the chemokine receptor CXCR3 differentially control chemotaxis and inflammation | journal = Science Signaling | volume = 11 | issue = 555 | pages = eaaq1075 | date = November 2018 | pmid = 30401786 | pmc = 6329291 | doi = 10.1126/scisignal.aaq1075 }} and possibly Celiac Disease.{{cite journal | vauthors = Lammers KM, Lu R, Brownley J, Lu B, Gerard C, Thomas K, Rallabhandi P, Shea-Donohue T, Tamiz A, Alkan S, Netzel-Arnett S, Antalis T, Vogel SN, Fasano A | title = Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3 | journal = Gastroenterology | volume = 135 | issue = 1 | pages = 194–204.e3 | date = July 2008 | pmid = 18485912 | pmc = 2653457 | doi = 10.1053/j.gastro.2008.03.023 }} It may also have implications in lung tissue repair after exposure to cigarette smoking.{{cite journal | vauthors = Nie L, Liu ZJ, Zhou WX, Xiang RL, Xiao Y, Lu B, Pang BS, Gao JM | title = Chemokine receptor CXCR3 is important for lung tissue damage and airway remodeling induced by short-term exposure to cigarette smoking in mice | journal = Acta Pharmacologica Sinica | volume = 31 | issue = 4 | pages = 436–442 | date = April 2010 | pmid = 20208554 | pmc = 4007663 | doi = 10.1038/aps.2009.192 | doi-access = free }} Development of agents to block CXCR3-ligand interactions may provide new ways to treat these diseases. In addition, CXCR3 has been implicated in inflammatory brain damage in central nervous system (CNS) infections{{cite journal | vauthors = Xu J, Neal LM, Ganguly A, Kolbe JL, Hargarten JC, Elsegeiny W, Hollingsworth C, He X, Ivey M, Lopez R, Zhao J, Segal B, Williamson PR, Olszewski MA | title = Chemokine receptor CXCR3 is required for lethal brain pathology but not pathogen clearance during cryptococcal meningoencephalitis | journal = Science Advances | volume = 6 | issue = 25 | pages = eaba2502 | date = June 2020 | pmid = 32596454 | pmc = 7299622 | doi = 10.1126/sciadv.aba2502 | bibcode = 2020SciA....6.2502X }}{{cite journal | vauthors = Campanella GS, Tager AM, El Khoury JK, Thomas SY, Abrazinski TA, Manice LA, Colvin RA, Luster AD | title = Chemokine receptor CXCR3 and its ligands CXCL9 and CXCL10 are required for the development of murine cerebral malaria | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 12 | pages = 4814–4819 | date = March 2008 | pmid = 18347328 | pmc = 2290783 | doi = 10.1073/pnas.0801544105 | doi-access = free | bibcode = 2008PNAS..105.4814C }}{{cite journal | vauthors = Sorensen EW, Lian J, Ozga AJ, Miyabe Y, Ji SW, Bromley SK, Mempel TR, Luster AD | title = CXCL10 stabilizes T cell-brain endothelial cell adhesion leading to the induction of cerebral malaria | journal = JCI Insight | volume = 3 | issue = 8 | date = April 2018 | pmid = 29669942 | pmc = 5931132 | doi = 10.1172/jci.insight.98911 }}{{cite journal | vauthors = Hirako IC, Ataide MA, Faustino L, Assis PA, Sorensen EW, Ueta H, Araújo NM, Menezes GB, Luster AD, Gazzinelli RT | title = Splenic differentiation and emergence of CCR5⁺CXCL9⁺CXCL10⁺ monocyte-derived dendritic cells in the brain during cerebral malaria | journal = Nature Communications | volume = 7 | issue = 1 | pages = 13277 | date = November 2016 | pmid = 27808089 | pmc = 5097164 | doi = 10.1038/ncomms13277 | bibcode = 2016NatCo...713277H }}{{cite journal | vauthors = Amin DN, Rottenberg ME, Thomsen AR, Mumba D, Fenger C, Kristensson K, Büscher P, Finsen B, Masocha W | title = Expression and role of CXCL10 during the encephalitic stage of experimental and clinical African trypanosomiasis | journal = The Journal of Infectious Diseases | volume = 200 | issue = 10 | pages = 1556–1565 | date = November 2009 | pmid = 19827943 | doi = 10.1086/644597 | doi-access = free }}{{cite journal | vauthors = Mehla R, Bivalkar-Mehla S, Nagarkatti M, Chauhan A | title = Programming of neurotoxic cofactor CXCL-10 in HIV-1-associated dementia: abrogation of CXCL-10-induced neuro-glial toxicity in vitro by PKC activator | journal = Journal of Neuroinflammation | volume = 9 | issue = 1 | pages = 239 | date = October 2012 | pmid = 23078780 | pmc = 3533742 | doi = 10.1186/1742-2094-9-239 | doi-access = free }}

Evidence from pre-clinical and clinical investigations has revealed the involvement of CXCR3 and its ligands in several cardiovascular diseases (CVDs) of diverse etiologies including atherosclerosis, hypertension, Kawasaki disease, myocarditis, dilated cardiomyopathies, Chagas, cardiac hypertrophy and heart failure, as well as in heart transplant rejection and transplant coronary artery disease (CAD).{{cite journal | vauthors = Altara R, Mallat Z, Booz GW, Zouein FA | title = The CXCL10/CXCR3 Axis and Cardiac Inflammation: Implications for Immunotherapy to Treat Infectious and Noninfectious Diseases of the Heart | journal = Journal of Immunology Research | volume = 2016 | pages = 4396368 | date = 2016 | pmid = 27795961 | pmc = 5066021 | doi = 10.1155/2016/4396368 | doi-access = free }}

CXCL9-10-11 have been recognized to be valid biomarkers for the development of heart failure and left ventricular dysfunction in two pilot studies, suggesting an underlining correlation between levels of the interferon (IFN)-γ-inducible chemokines and the development of adverse cardiac remodeling.{{cite journal | vauthors = Altara R, Gu YM, Struijker-Boudier HA, Thijs L, Staessen JA, Blankesteijn WM | title = Left Ventricular Dysfunction and CXCR3 Ligands in Hypertension: From Animal Experiments to a Population-Based Pilot Study | journal = PLOS ONE | volume = 10 | issue = 10 | pages = e0141394 | date = 2015 | pmid = 26506526 | pmc = 4624781 | doi = 10.1371/journal.pone.0141394 | doi-access = free | bibcode = 2015PLoSO..1041394A }}

{{cite journal | vauthors = Altara R, Manca M, Hessel MH, Gu Y, van Vark LC, Akkerhuis KM, Staessen JA, Struijker-Boudier HA, Booz GW, Blankesteijn WM | title = CXCL10 Is a Circulating Inflammatory Marker in Patients with Advanced Heart Failure: a Pilot Study | journal = Journal of Cardiovascular Translational Research | volume = 9 | issue = 4 | pages = 302–314 | date = August 2016 | pmid = 27271043 | doi = 10.1007/s12265-016-9703-3 | s2cid = 41188765 }}

Recent reports indicate that there is a significant interest for the identification of small-molecule antagonists of CXCR3.{{cite journal | vauthors = Watson RJ, Allen DR, Birch HL, Chapman GA, Galvin FC, Jopling LA, Knight RL, Meier D, Oliver K, Meissner JW, Owen DA, Thomas EJ, Tremayne N, Williams SC | title = Development of CXCR3 antagonists. Part 3: Tropenyl and homotropenyl-piperidine urea derivatives | journal = Bioorganic & Medicinal Chemistry Letters | volume = 18 | issue = 1 | pages = 147–151 | date = January 2008 | pmid = 18032038 | doi = 10.1016/j.bmcl.2007.10.109 }} Several small molecules {{cite journal | vauthors = Watson RJ, Allen DR, Birch HL, Chapman GA, Hannah DR, Knight RL, Meissner JW, Owen DA, Thomas EJ | title = Development of CXCR3 antagonists. Part 2: Identification of 2-amino(4-piperidinyl)azoles as potent CXCR3 antagonists | journal = Bioorganic & Medicinal Chemistry Letters | volume = 17 | issue = 24 | pages = 6806–6810 | date = December 2007 | pmid = 17964154 | doi = 10.1016/j.bmcl.2007.10.029 }} were found to constitute a promising series of functional antagonists of CXCR3 that could be developed into new therapeutic agents for the treatment of inflammatory disorders such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis and diabetes. More recently the first QSAR study concerning antagonists of CXCR3 has been published in the literature. The in silico model provides a time- and cost-effective tool for the screening of existing and virtual libraries of small molecules as well as for designing of novel molecules of desired activity.{{cite journal | vauthors = Afantitis A, Melagraki G, Sarimveis H, Igglessi-Markopoulou O, Kollias G | title = A novel QSAR model for predicting the inhibition of CXCR3 receptor by 4-N-aryl-[1,4] diazepane ureas | journal = European Journal of Medicinal Chemistry | volume = 44 | issue = 2 | pages = 877–884 | date = February 2009 | pmid = 18619714 | doi = 10.1016/j.ejmech.2008.05.028 }}

• Chemokine receptors
• Chemokine
• Cluster of differentiation

{{reflist|30em}}

• {{cite web | url = http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2214 | title = Chemokine Receptors: CXCR3 | work = IUPHAR Database of Receptors and Ion Channels | publisher = International Union of Basic and Clinical Pharmacology }}
• {{MeshName|CD183+Antigen}}
• {{UCSC gene info|CXCR3}}

{{Chemokine receptors|state=collapsed}}

{{Clusters of differentiation}}

{{Chemokine receptor modulators}}

Category:Clusters of differentiation