CXCL9

CXCL9, also known as C-X-C motif chemokine 9 or "monokine induced by gamma interferon" or MIG, is a small, 125 amino acid chemokine from the group of CXC chemokines, which is primarily induced by gamma interferon.

Chemokines, a subgroup of cytokines, are small (size between 8 and 10 kDa), chemotactically active proteins (signaling proteins). They are found in all vertebrates, some virus species and bacteria. Around 50 chemokines are currently known in humans. A strongly conserved structural feature of all chemokines is a fixed group of cysteine residues that is stabilized by 1 or 2 disulfide bridges. This key structural position in the molecule is responsible for their fixed 3-dimensional structure (see chemokines below).

In the CC chemokines, the cysteines follow each other directly (see figure), in the CXC chemokines they are separated by 1 amino acid, in the CXXXC chemokines by 3 other amino acids. Chemokines are produced and secreted by a large number of immune cells. They transmit their signals by means of specific chemokine receptors via G proteins.

The fact that chemokines and their receptors are not only expressed on inflammatory cells, but also by epithelial cells, mesenchymal cells, neurogenic cells, endothelial cells and various tumor cell lines suggests that they participate in numerous regulatory cell functions.

CXCL9 is encoded by the CXCL9 gene, which in humans is located on chromosome 4q21.1 together with the genes for CXCL10 and CXCL11. Like the homologous chemokines CXCL10 and CXCL11, CXCL binds to the G-protein-coupled chemokine receptor CXCR3 and has a chemotactic effect on T cells but not on neutrophil granulocytes.

The CXCR3 receptor is also expressed in pneumocytes and in pulmonary and hepatic fibroblasts. A variant of the CXCR3 receptor has been described, which has been named CXCR3-B (the previously known CXCR3 receptor is to be named CXCR3A in the future). CXCR3B mediates the angiostatic activity of CXCR3 ligands and also acts as a functional receptor for CXCL4.

CXCL9 is formed and secreted in dermal fibroblasts and venous endothelial cells. The induction can be enhanced by TNF-alpha.

The enzymes gelatinase B / matrix metalloproteinase 9 inhibit the function of CXCL10 by cleaving CXCL9 at 3 different sites in its extended carboxy-terminal region. In cultures of human microvascular endothelial cells, growth is inhibited by CXCL9, CXCL10, CXCL11 and CXCL4.

CXCL9 is a key immunoregulatory factor for various infections. CXCL9 is a key immunoregulatory chemokine for various infections. For example, in patients with kidney transplants infected by polyomavirus BK, serum CXCL9 levels are significantly elevated.

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

CXCL9 is also being discussed as a predictive biomarker in chronic GvHD (Chen T et al. 2019).

Heart failure and left ventricular dysfunction: CXCL9 and the homologous chemokines CXCL -10, -11 have been shown to be valid biomarkers for the development of heart failure and left ventricular dysfunction. Serum MIG levels (CXCL9) have been shown to be associated with the severity of coronary heart disease.

Psoriasis: In a larger study, serum levels of CXCL9, CCL5, osteopontin (OPN) were shown to be elevated in psoriatic patients compared to a healthy control group. These findings were independent of the degree of obesity of the patients.

GVHD: Serum levels of CXCL9 are elevated in GVHD. CXCL9 could serve as a (however unspecific) biomarker for GVHD.

Liver cirrhosis and portal hypertension: CXCL9 and other chemokines play an important role in the pathogenesis of liver cirrhosis. CXCL9 is significantly increased in patients with liver cirrhosis and severe portal hypertension. CXCL9 levels are associated with a poor prognosis.

Malignancies: CXCL9 is also expressed in some malignant tumors.

Rheumatoid arthritis: Chemokines (CXCL) and their receptors play an important role in the pathogenesis of rheumatoid arthritis (RA). In one study it was shown that "Single nucleotide polymorphisms -SNPs- in the CXCL10 gene ((rs8878 A>G) but not in the CXCL9 gene are associated with rheumatoid arthritis.

1. Altara R et al. (2015) Left Ventricular Dysfunction and CXCR3 Ligands in Hypertension: From Animal Experiments to a Population-Based Pilot Study. PLoS One 10:e0141394.
2. Berres ML et al. CXCL9 is a prognostic marker in patients with liver cirrhosis receiving transjugular intrahepatic portosystemic shunt. J Hepatol 62:332-339.

3. Chen T et al. (2019) The clinical observation of serum specific biomarkers in patients with chronic graft-versus-host disease. Zhonghua Xue Ye Xue Za Zhi 40: 948-952.

4. Duarte GV et al. (2015) Osteopontin, CCL5 and CXCL9 are independently associated with psoriasis, regardless of the presence of obesity. Cytokine 74:287-292.

5. Kariminik A et al. (2016) CXCL9 expression and polyomavirus BK infectivity in renal transplant patients with nephropathy. Cell Mol Biol (Noisy-le-grand) 62:104-108.
6. Kitko CL et al. (2014) Plasma CXCL9 elevations correlate with chronic GVHD diagnosis.Blood 123:786-793.
7. Kotrych D et al. (2015) CXCL9 and CXCL10 gene polymorphisms in patients with rheumatoid arthritis. Rheumatol Int 35:1319-1323.
8. Liang Y et al. (2017) Serum Monokines Induced by Gamma Interferon Is Associated With Severity of Coronary Artery Disease.Int Heart J 58:24-29.
9. Ohtani H et al. (2009) Abundant expression of CXCL9 (MIG) by stromal cells that include dendritic cells and accumulation of CXCR3+ T cells in lymphocyte-rich gastric carcinoma. J Pathol 217:21-31.

10. Torok KS et al. (2019) Immunopathogenesis of Pediatric Localized Scleroderma. Front Immunol 10:908.