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CXCL9

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CXCL9
Identifiers
AliasesCXCL9, CMK, Humig, MIG, SCYB9, crg-10, C-X-C motif chemokine ligand 9
External IDsOMIM: 601704; MGI: 1352449; HomoloGene: 1813; GeneCards: CXCL9; OMA:CXCL9 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

4283

17329

Ensembl

ENSG00000138755

ENSMUSG00000029417

UniProt

Q07325

P18340

RefSeq (mRNA)

NM_002416

NM_008599

RefSeq (protein)

NP_002407

NP_032625

Location (UCSC)Chr 4: 76 – 76.01 MbChr 5: 92.47 – 92.48 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Chemokine (C-X-C motif) ligand 9 (CXCL9) is a small cytokine belonging to the CXC chemokine family that is also known as monokine induced by gamma interferon (MIG). The CXCL9 is one of the chemokine which plays role to induce chemotaxis, promote differentiation and multiplication of leukocytes, and cause tissue extravasation.[5]

It is closely related to two other CXC chemokines called CXCL10 and CXCL11, whose genes are located near the gene for CXCL9 on human chromosome 4.[6][7] CXCL9, CXCL10 and CXCL11 all elicit their chemotactic functions by interacting with the chemokine receptor CXCR3.[8]

Structre

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Chemokine (C-X-C motif) ligand 9 (CXCL9) exhibits the classic structure of CXC chemokines, characterized by a short and flexible N-terminal region, a well-ordered core stabilized by two disulfide bonds, three antiparallel beta-strands, and a C-terminal alpha-helix.[9] This conserved tertiary structure provides both stability and the necessary conformational flexibility at the N- and C-termini, enabling effective interactions with its receptor, CXCR3, and facilitating signal transduction essential for immune cell migration and activation.[9] The structural core is highly conserved among CXC chemokines, while variations in the loop regions contribute to differences in receptor binding and functional specificity.[9]

Function

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The CXCL9/CXCR3 receptor regulates immune cell migration, differentiation, and activation. Immune reactivity occurs through recruitment of immune cells, such as cytotoxic lymphocytes (CTLs), natural killer (NK) cells, NKT cells, and macrophages. Th1 polarization also activates the immune cells in response to IFN-γ.[10] Tumor-infiltrating lymphocytes are a key for clinical outcomes and prediction of the response to checkpoint inhibitors.[11] In vivo studies suggest the axis plays a tumorigenic role by increasing tumor proliferation and metastasis.[citation needed] CXCL9 predominantly mediates lymphocytic infiltration to the focal sites and suppresses tumor growth.[12]

Immune modulation

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In immune cell differentiation, several reports indicate that CXCL9 promotes T helper 1 (Th1) polarization through CXCR3.[13] An in vivo model by Zohar et al. demonstrated that CXCL9 increased the transcription of T-bet and RORγ, leading to the polarization of Foxp3− type 1 regulatory (Tr1) cells or Th17 cells from naïve T cells via STAT1, STAT4, and STAT5 phosphorylation.[13]

Several studies have shown that tumor-associated macrophages (TAMs) exert modulatory effects in the tumor microenvironment (TME), with the CXCL9/CXCR3 axis influencing TAM polarization. TAMs can exhibit opposing effects: M1 macrophages promote anti-tumor activity, while M2 macrophages support tumor progression. Oghumu et al. found that mice deficient in CXCR3 displayed increased IL-4 production and M2 polarization in a murine breast cancer model, accompanied by reduced innate and immune cell-mediated anti-tumor responses.[14]

Regarding immune cell activation, CXCL9 stimulates Th1 polarization and activation, leading to the production of IFN-γ, TNF-α, and IL-2. This enhances anti-tumor immunity by activating cytotoxic T lymphocytes (CTLs), NK cells, and macrophages.[15] Additionally, the IFN-γ-dependent immune activation loop further promotes CXCL9 release.[5] Immune cells such as Th1 cells, CTLs, NK cells, and NKT cells exert anti-tumor effects against cancer cells via paracrine CXCL9/CXCR3 signaling in tumor models.[12] In contrast, autocrine CXCL9/CXCR3 signaling in cancer cells has been implicated in promoting cancer cell proliferation, angiogenesis, and metastasis.[citation needed]

Immune checkpoint regulation

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The relationship between the CXCL9/CXCR3 axis and the PD-L1/PD-1 pathway is important in immune regulation. Programmed cell death protein 1 (PD-1) expression is increased on T cells within the tumor site compared to T cells in peripheral blood. Anti-PD-1 therapy can inhibit "immune escape" and enhance immune activation.[16] Peng et al. demonstrated that anti-PD-1 therapy not only enhanced T cell-mediated tumor regression but also increased the expression of IFN-γ, though not CXCL9, in bone marrow-derived cells.[16] Blockade of the PD-L1/PD-1 axis in T cells may induce a positive feedback loop at the tumor site through the CXCL9/CXCR3 axis. Additionally, treatment with an anti-CTLA4 antibody led to a significant upregulation of this axis in pretreatment melanoma lesions from patients who exhibited a favorable clinical response to ipilimumab.[17]

Clinical signficance

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Biomarkers

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CXCL9, -10, -11 have proven to be valid biomarkers for the development of heart failure and left ventricular dysfunction, suggesting an underlining pathophysiological relation between levels of these chemokines and the development of adverse cardiac remodeling.[18][19]

This chemokine has also been associated as a biomarker for diagnosing Q fever infections.[20]

Melanoma

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CXCL9 has also been identified as candidate biomarker of adoptive T cell transfer therapy in metastatic melanoma.[21] The role of CXCL9/CXCR3 in TME and immune response - this plays a critical role in immune activation through paracrine signaling, impacting efficacy of cancer treatments.[5]

Interactions

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CXCL9 has been shown to interact with CXCR3.[22][23]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000138755 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000029417 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b c Tokunaga R, Zhang W, Naseem M, Puccini A, Berger MD, Soni S, et al. (February 2018). "CXCL9, CXCL10, CXCL11/CXCR3 axis for immune activation - A target for novel cancer therapy". Cancer Treatment Reviews. 63: 40–47. doi:10.1016/j.ctrv.2017.11.007. PMC 5801162. PMID 29207310.
  6. ^ Lee HH, Farber JM (1996). "Localization of the gene for the human MIG cytokine on chromosome 4q21 adjacent to INP10 reveals a chemokine "mini-cluster"". Cytogenetics and Cell Genetics. 74 (4): 255–258. doi:10.1159/000134428. PMID 8976378.
  7. ^ O'Donovan N, Galvin M, Morgan JG (1999). "Physical mapping of the CXC chemokine locus on human chromosome 4". Cytogenetics and Cell Genetics. 84 (1–2): 39–42. doi:10.1159/000015209. PMID 10343098. S2CID 8087808.
  8. ^ Tensen CP, Flier J, Van Der Raaij-Helmer EM, Sampat-Sardjoepersad S, Van Der Schors RC, Leurs R, et al. (May 1999). "Human IP-9: A keratinocyte-derived high affinity CXC-chemokine ligand for the IP-10/Mig receptor (CXCR3)". The Journal of Investigative Dermatology. 112 (5): 716–722. doi:10.1046/j.1523-1747.1999.00581.x. PMID 10233762.
  9. ^ a b c Valdés N, Espinoza D, Pareja-Barrueto C, Olate N, Barraza-Rojas F, Benavides-Larenas A, et al. (2024). "Expression and regulation of the CXCL9-11 chemokines and CXCR3 receptor in Atlantic salmon (Salmo salar)". Frontiers in Immunology. 15: 1455457. doi:10.3389/fimmu.2024.1455457. PMC 11410577. PMID 39301034.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  10. ^ Schoenborn JR, Wilson CB (2007). "Regulation of interferon-gamma during innate and adaptive immune responses". Advances in Immunology. 96. Elsevier: 41–101. doi:10.1016/s0065-2776(07)96002-2. ISBN 978-0-12-373709-0. PMID 17981204.
  11. ^ Fernandez-Poma SM, Salas-Benito D, Lozano T, Casares N, Riezu-Boj JI, Mancheño U, et al. (July 2017). "+ T cells Expressing PD-1 Improves the Efficacy of Adoptive T-cell Therapy". Cancer Research. 77 (13): 3672–3684. doi:10.1158/0008-5472.CAN-17-0236. PMID 28522749.
  12. ^ a b Gorbachev AV, Kobayashi H, Kudo D, Tannenbaum CS, Finke JH, Shu S, et al. (2007-02-15). "CXC Chemokine Ligand 9/Monokine Induced by IFN- Production by Tumor Cells Is Critical for T Cell-Mediated Suppression of Cutaneous Tumors". Journal of Immunology. 178 (4). Baltimore, Md.: 2278–2286. doi:10.4049/jimmunol.178.4.2278. ISSN 0022-1767. PMID 17277133.
  13. ^ a b Zohar Y, Wildbaum G, Novak R, Salzman AL, Thelen M, Alon R, et al. (May 2014). "CXCL11-dependent induction of FOXP3-negative regulatory T cells suppresses autoimmune encephalomyelitis". The Journal of Clinical Investigation. 124 (5): 2009–2022. doi:10.1172/JCI71951. PMC 4001543. PMID 24713654. (This paper currently has an expression of concern, see doi:10.1172/JCI97015, PMID 28846074. If this is an intentional citation to a such a paper, please replace {{expression of concern|...}} with {{expression of concern|...|intentional=yes}}.)
  14. ^ Oghumu S, Varikuti S, Terrazas C, Kotov D, Nasser MW, Powell CA, et al. (September 2014). "CXCR3 deficiency enhances tumor progression by promoting macrophage M2 polarization in a murine breast cancer model". Immunology. 143 (1): 109–119. doi:10.1111/imm.12293. PMC 4137960. PMID 24679047.
  15. ^ Mosser DM, Edwards JP (December 2008). "Exploring the full spectrum of macrophage activation". Nature Reviews. Immunology. 8 (12): 958–969. doi:10.1038/nri2448. PMC 2724991. PMID 19029990.
  16. ^ a b Peng W, Liu C, Xu C, Lou Y, Chen J, Yang Y, et al. (October 2012). "PD-1 blockade enhances T-cell migration to tumors by elevating IFN-γ inducible chemokines". Cancer Research. 72 (20): 5209–5218. doi:10.1158/0008-5472.CAN-12-1187. PMC 3476734. PMID 22915761.
  17. ^ Ji RR, Chasalow SD, Wang L, Hamid O, Schmidt H, Cogswell J, et al. (July 2012). "An immune-active tumor microenvironment favors clinical response to ipilimumab". Cancer Immunology, Immunotherapy : CII. 61 (7): 1019–1031. doi:10.1007/s00262-011-1172-6. PMC 11028506. PMID 22146893. S2CID 8464711.
  18. ^ Altara R, Gu YM, Struijker-Boudier HA, Thijs L, Staessen JA, Blankesteijn WM (2015). "Left Ventricular Dysfunction and CXCR3 Ligands in Hypertension: From Animal Experiments to a Population-Based Pilot Study". Plos One. 10 (10): e0141394. Bibcode:2015PLoSO..1041394A. doi:10.1371/journal.pone.0141394. PMC 4624781. PMID 26506526.
  19. ^ Altara R, Manca M, Hessel MH, Gu Y, van Vark LC, Akkerhuis KM, et al. (August 2016). "CXCL10 Is a Circulating Inflammatory Marker in Patients with Advanced Heart Failure: a Pilot Study". Journal of Cardiovascular Translational Research. 9 (4): 302–314. doi:10.1007/s12265-016-9703-3. PMID 27271043. S2CID 41188765.
  20. ^ Jansen AF, Schoffelen T, Textoris J, Mege JL, Nabuurs-Franssen M, Raijmakers RP, et al. (August 2017). "CXCL9, a promising biomarker in the diagnosis of chronic Q fever". BMC Infectious Diseases. 17 (1): 556. doi:10.1186/s12879-017-2656-6. PMC 5551022. PMID 28793883.
  21. ^ Bedognetti D, Spivey TL, Zhao Y, Uccellini L, Tomei S, Dudley ME, et al. (October 2013). "CXCR3/CCR5 pathways in metastatic melanoma patients treated with adoptive therapy and interleukin-2". British Journal of Cancer. 109 (9): 2412–2423. doi:10.1038/bjc.2013.557. PMC 3817317. PMID 24129241.
  22. ^ Lasagni L, Francalanci M, Annunziato F, Lazzeri E, Giannini S, Cosmi L, et al. (June 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". The Journal of Experimental Medicine. 197 (11): 1537–1549. doi:10.1084/jem.20021897. PMC 2193908. PMID 12782716.
  23. ^ Weng Y, Siciliano SJ, Waldburger KE, Sirotina-Meisher A, Staruch MJ, Daugherty BL, et al. (July 1998). "Binding and functional properties of recombinant and endogenous CXCR3 chemokine receptors". The Journal of Biological Chemistry. 273 (29): 18288–18291. doi:10.1074/jbc.273.29.18288. PMID 9660793.

Further reading

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