CXCR3 gene

The CXCR3 gene (CXCR3 stands for: C-X-C Motif Chemokine Receptor 3) is a protein-coding gene located on chromosome Xq13.1. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. One of the isoforms (CXCR3-B) shows a high affinity for binding to the chemokine CXCL4/PF4.

The CXCR3 gene encodes a G protein-coupled receptor with selectivity for three chemokines, designated CXCL9/Mig (interferon-g induced monokine), CXCL10/IP10 (interferon-gamma inducible 10 kDa protein) and CXCL11/I-TAC (interferon-gamma inducible T cell A chemoattractant).

Binding of chemokines to this protein triggers cellular responses involved in leukocyte trafficking, most notably integrin activation, cytoskeletal changes and chemotactic migration.

Diseases associated with CXCR3 include cutaneous lupus erythematosus and pulmonary sarcoidosis.

(Isoform 1): Receptor for the C-X-C chemokines CXCL9, CXCL10 and CXCL11 and mediates proliferation, survival and angiogenic activity of human mesangial cells (HMC) via a heterotrimeric G-protein signaling pathway. Binds to CCL21. Likely promotes the chemotaxis response of cells. For example, the CXCL10 gene is an antimicrobial gene that encodes a chemokine of the CXC subfamily. Binding of the CXCL10 protein to the CXCR3 receptor leads to pleiotropic effects, including stimulation of monocytes, migration of natural killer and T cells, and modulation of adhesion molecule expression. Mechanistically, binding of CXCL10 to the CXCR3 receptor activates G protein-mediated signaling and leads to downstream activation of the phospholipase C-dependent pathway, an increase in intracellular calcium production and actin reorganization (Smit MJ et al. 2003).

In turn, activated Th1 lymphocytes are recruited to the sites of inflammation (Cheeran MC et al. 2003).

Activation of the CXCL10/CXCR3 axis also plays an important role in neurons in response to brain injury by activating and directing microglia, the resident macrophage population of the central nervous system, to the site of the lesion. This recruitment is an essential element for neuronal reorganization.

[Isoform 2]: Receptor for the C-X-C chemokine CXCL4 and also mediates the inhibitory effect of CXCL9, CXCL10 and CXCL11 on the proliferation, survival and angiogenic activity of human microvascular endothelial cells (HMVEC) via a cAMP-mediated signaling pathway (Lasagni L et al. 2003). Does not promote the chemotaxis response of cells. Interaction with CXCL4 or CXCL10 leads to activation of the p38MAPK signaling pathway and contributes to inhibition of angiogenesis. Overexpression in kidney cancer cells downregulates the expression of the anti-apoptotic protein HMOX1 and promotes apoptosis.

[Isoform 3]: Mediates the activity of CXCL11.

1. Angiolillo AL et al. (1995) Human interferon-inducible protein 10 is a potent inhibitor of angiogenesis in vivo. J Exp Med 182:155-162.
2. Cheeran MC et al. (2003) CXCL10 production from cytomegalovirus-stimulated microglia is regulated by both human and viral interleukin-10. J Virol 77:4502-4515.
3. Lasagni L et al. (2003) An alternatively spliced variant of CXCR3 mediates the inhibition of endothelial cell growth induced by IP-10, Mig, and I-TAC, and acts as functional receptor for platelet factor 4. J Exp Med 197:1537-1549.
4. Sidahmed AM et al. (2012) CXCL10 contributes to p38-mediated apoptosis in primary T lymphocytes in vitro. Cytokine 59:433-41.
5. Smit MJ et al. (2003) 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. Blood 102:1959-1965.