CXCR3

Official Full Name

C-X-C motif chemokine receptor 3

Organism

Homo sapiens

GeneID

2833

Background

This gene encodes a G protein-coupled receptor with selectivity for three chemokines, termed CXCL9/Mig (monokine induced by interferon-g), CXCL10/IP10 (interferon-g-inducible 10 kDa protein) and CXCL11/I-TAC (interferon-inducible T cell a-chemoattractant). Binding of chemokines to this protein induces cellular responses that are involved in leukocyte traffic, most notably integrin activation, cytoskeletal changes and chemotactic migration. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. One of the isoforms (CXCR3-B) shows high affinity binding to chemokine, CXCL4/PF4 (PMID:12782716). [provided by RefSeq, Jun 2011]

Synonyms

GPR9; MigR; CD182; CD183; Mig-R; CKR-L2; CMKAR3; IP10-R;

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Detailed Information

Recent Research Progress

The CXC motif chemokine receptor 3 (CXCR3) gene encodes a G protein-coupled receptor with selectivity for three chemokines: CXC motif chemokine ligand 9 (CXCL9) or MIG (IFNγ-induced single Nuclear factor), CXCL10 or IP10 (IFNγ-induced 10kDa protein) and CXCL11 or I-TAC (IFN-inducible T cell alpha-chemoattractant). CXCR3 plays an important role in regulating leukocyte trafficking; in fact, the binding of chemokines induces cellular responses that are involved in leukocyte trafficking, most notably integrin activation, cytoskeletal changes and chemotactic migration. CXCR3 is expressed primarily on activated T lymphocytes and NK cells as well as on some epithelial and endothelial cells. It has been shown to play an important role in tumorigenesis and tumor progression in many malignancies.

CXCR3 and GC

Recently, studies have found that CXCR3 overexpression occurs in gastric cancer (GC) tissues compared to non-tumor gastric tissue. High levels of CXCR3 expression have been found to be inversely associated with depth of invasion and metastasis and are directly related to improve overall survival. In addition, multivariate analysis showed that high CXCR3 expression was an independent prognostic factor in patients with GC. Messenger RNA expression of both the CXCR3 variants, CXCR3-A and CXCR3-B, were up-regulated in GC tissues, although CXCR3-B messenger RNA expression was significantly higher than CXCR3-A, and the ratio of average CXCR3-B to CXCR3-A was 1.80. CXCR3-B protein expression was also up-regulated in GC tissues. In conclusion, studies have shown that it was possible to use CXCR3 overexpression as a prognostic marker for GC and to participate in the up-regulation of CXCR3-B, thereby contributing to the prognosis of patients with GC.

CXCR3 and acute glaucoma

Acute glaucoma is the main cause of irreversible blindness in East Asia. Recent studies have demonstrated that activation of the CXCL10/CXCR3 axis, which mediates the recruitment and activation of inflammatory cells, plays a key role in the mouse model of acute glaucoma. After IOP-induced retinal ischemia, the mRNA and protein expression levels of CXCL10 and CXCR3 were significantly increased. Blocking the CXCR3 gene by deleting the CXCR3 gene significantly attenuates the up-regulation of inflammatory molecules (interleukin-1β and E-selectin) induced by ischemic injury and inhibits the recruitment of microglia/monocytes to the superficial layer of the retina. In contrast, intravitreal delivery of CXCL10 increased leukocyte recruitment and retinal cell apoptosis. Inhibition of endoplasmic reticulum (ER) stress with a chemical chaperone partially blocked up-regulation of CXCL10 induced by ischemic injury, whereas induction of ER stress by tunicamycin enhanced CXCL10 expression in retinal and primary retinal ganglion cells. Interestingly, deletion of CXCR3 attenuated ER stress-induced retinal cell death. Taken together, these results suggest that activation of the CXCL10/CXCR3 pathway by ER stress drugs plays an important role in high IOP-induced post-ischemic retinal inflammation and neuronal damage.

CXCR3 and ACD

Persistent itching is a common symptom of allergic contact dermatitis (ACD) and represents a significant health burden. The chemokine CXCL10 is mainly produced by epithelial cells during ACD. Although the chemokine CXCL10 and its receptor CXCR3 are involved in the pathophysiology of ACD, it has been largely undeveloped for itching and pain associated with this disease. Recent studies have shown that CXCL10 and CXCR3 mRNA, protein and signaling activity were upregulated in the dorsal root ganglion (DRG) after contact hypersensitivity (CHS), a murine model of ACD, induced by squaric acid dibutylester. CXCL10 directly activates a subset of skin DRG neurons that innervate the CHS region via neuronal CXCR3. In behavioral testing, CXCR3 antagonists attenuated spontaneous pruritus rather than pain-like behavior against the CHS site. Injection of CXCL10 into the CHS site caused localized pruritus-but not pain-like behavior, but no CXCL10-induced behavioral patterns were observed in control mice. These results indicate that CXCL10/CXCR3 signaling mediates allergic pruritus but does not mediate inflammatory pain in the case of skin inflammation. Therefore, up-regulation of CXCL10/CXCR3 signaling in sensory neurons may lead to itching associated with ACD. Signaling for CXCL10/CXCR3 may be beneficial for the treatment of allergic pruritus.

In addition, increased expression of CXCR3 is associated with poor prognosis in patients with breast cancer, melanoma, colon and kidney cancer. Of the three variants of CXCR3-CXCR3A, CXCR3B and CXCR3-alt, two major variants, CXCR3A and CXCR3B, have been reported to induce opposite physiological functions. CXCR3A appears to mediate tumor-promoting effects, including cell proliferation, survival, chemotaxis, invasion and metastasis; whereas CXCR3B mediates anti-tumor effects by promoting growth inhibition, apoptosis and vascular degeneration. It is worth noting that a recent study reported that CXCR3B may promote stem cell function; while CXCR3A exhibits a function that promotes proliferation and promotes metastasis. Therefore, further study of the function of CXCR3 plays a major role in the diagnosis and treatment of related diseases.

References:

Lleo, et al. DNA methylation profiling of the X chromosome reveals an aberrant demethylation on CXCR3 promoter in primary biliary cirrhosis. Clinical Epigenetics, 2015, 7:61.
Hu Min, et al. Overexpression of the chemokine receptor CXCR3 and its correlation with favorable prognosis in gastric cancer. Human Pathology, 2015, 46(12):1872-1880.
Li Kai, et al. Impact of chemokine receptor CXCR3 on tumor-infiltrating lymphocyte recruitment associated with favorable prognosis in advanced gastric cancer. International Journal of Clinical And Experimental Pathology, 2015, 8(11):14725-14732.
Y Ha, et al. Endoplasmic reticulum stress-regulated CXCR3 pathway mediates inflammation and neuronal injury in acute glaucoma. Cell Death and Disease, 2015, 6:e1900.
Qu Lintao, et al. CXCR3 chemokine receptor signaling mediates itch in experimental allergic contact dermatitis. Pain. 2015, 156(9):1737–1746.
Zhu GQ, et al. CXCR3 as a molecular target in breast cancer metastasis: inhibition of tumor cell migration and promotion of host anti-tumor immunity. Oncotarget, 2015, 6(41):43408-43419.

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