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

Together with the cytokines CXCL10 and CXCL11, the chemokine CXCL9 plays a pathogenetic role in selected diseases of the central nervous system, such as tick-borne encephalitis (TBE), neuroborreliosis (NB), Alzheimer's disease (AD) and multiple sclerosis (MS).

O'Brien et al. analyzed transcriptional and cytokine profiles in 87 adult morphea patients and 26 healthy controls and found an association of CXCL9 with disease severity in active morphea patients. The encoded chemokine was present at elevated levels in nearly half of the clientele along with Th1 cell cytokines (57%). CXCL9/10 studies also led to a new hypothesis about the development of circumscript scleroderma. As a result of cutaneous overproduction of IFN-gamma by cutaneous macrophages, a Th1 imbalance in the skin could contribute to the progression of the disease. Thus, local autoimmunity of the skin could be the driving force of the disease, in contrast to systemic dysregulation in SSc (O'Brien et al 2017).

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, as 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 one-way signaling. Furthermore, it is known that tumor cells express multiple chemokine receptors and secrete their ligands. The vast majority of these chemokines support tumor growth through different mechanisms, and it is believed that CXCL10 and possibly CXCL9 differ from other chemokines in their ability to inhibit tumor growth and enhance anti-tumor immunity. In addition, 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. Furthermore, they are not yet widely available in clinical practice.

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

1. O'Brien JC et al. (2017) Transcriptional and cytokine profiles identify CXCL9 as a biomarker of disease activity in morphea. J Invest Dermatol 137:1663-1670.
2. Karin N (2020) CXCR3 Ligands in Cancer and Autoimmunity, Chemoattraction of Effector T Cells, and Beyond. Front Immunol 29;11:976.
3. Koper OM et al. (2018) CXCL9, CXCL10, CXCL11, and their receptor (CXCR3) in neuroinflammation and neurodegeneration. Adv Clin Exp Med 27: 849-856.
4. Torok KS et al. (2019) Immunopathogenesis of Pediatric Localized Scleroderma. Front Immunol 10:908.