CXCL9 gene

The CXCL9 gene (CXCL9 stands for: C-X-C Motif Chemokine Ligand 9) is a protein coding gene localized to chromosome 4q21.1.

The CXCL9 gene belongs to a chemokine superfamily that encodes secreted proteins involved in immunoregulatory and inflammatory processes. It is likely that the encoded protein is involved in T cell transport. The encoded CXCL9- protein binds to C-X-C motif chemokine 3 (CXCR3) and is a chemoattractant for lymphocytes but not neutrophils. CXCR3 is a chemokine receptor with three ligands: CXCL9, CXCL10 and CXCL11. CXCL11 binds CXCR3 with a higher affinity than the other ligands, leading to internalization of the receptor.

Together with the cytokines CXCL10 and CXCL11, CXCL9 plays a pathogenetic role in selected central nervous system diseases, such as early summer meningoencephalitis (TBE), neuroborreliosis (NB), Alzheimer's disease (AD), and multiple sclerosis (MS). CXCL9, CXCL10, and CXCL11 lack glutamic acid-leucine-arginine (ELR) and are unique in that they are more closely related to each other than to any other chemokine. The chemokines are particularly involved in the Th1 response and in various diseases because their expression correlates with tissue infiltration of T cells. Their production is strongly stimulated by interferon gamma (IFN-υ), the most typical Th1 cytokine. They act by binding to the CXC3 receptor (Koper OM et al. 2018).

CXCR3 ligands appear to differentially regulate the biological function of T cells via unilateral signaling. Furthermore, tumor cells are known to express multiple chemokine receptors and secrete their ligands. The vast majority of these chemokines support tumor growth through distinct mechanisms.CXCL10 and possibly CXCL9 are thought to differ from other chemokines in their ability to inhibit tumor growth and enhance anti-tumor immunity. Moreover, a growing number of studies in various human cancers have shown a clear association between poor prognosis and low expression of CXCL10 at tumor sites and vice versa (Karin N 2020).

Recent prospective studies of serum cytokines in LS patients have identified potential blood markers of disease activity, including CXCL9 (Glaser Torok KS et al 2019). However, the clinical utility of these markers in PRS/ECDS patients is unclear. Further, they are not yet widely available in clinical practice.

Related signaling pathways include MIF-mediated glucocorticoid regulation and GPCR signaling (downstream). An important paralog of this gene is CXCL2.

1. Karin N (2020) CXCR3 Ligands in Cancer and Autoimmunity, Chemoattraction of Effector T Cells, and Beyond. Front Immunol 29;11:976.
2. Koper OM et al (2018) CXCL9, CXCL10, CXCL11, and their receptor (CXCR3) in neuroinflammation and neurodegeneration. Adv Clin Exp Med 27: 849-856.
3. Torok KS et al (2019) Immunopathogenesis of pediatric localized scleroderma. Front Immunol 10:908.