Table 1. Summary of the effects of each CXCR3 ligand in different organ systems and models of fibrosis.

Ligand	Organ	Disease	Experimental model	Species	Effect on fibroblasts/ fibrosis?	Study outcomes	Reference(s)
CXCL9	Heart	Myocardial infarction	Spontaneous; isoproterenol- induced	Human; Rat	Proliferation & migration	Increased fibrosis following MI; cytokines released by myocardium induced expression of CXCL9 which promoted fibroblast proliferation & migration	Lin et al., 2019
		Rheumatic fever	Spontaneous	Human	no direct effect shown	Increased migration of inflammatory infiltrates specifically to valves and correlated with amount of cardiac fibrosis	Faé et al., 2013
		Chagas cardiomyopathy	Spontaneous; infduced	Human; Beagle dog	no direct effect shown	Increased migration of inflammatory infiltrates to the heart; polymorphism CXCL9 rs10336 CC was associated with protection from progression to severe CCC	Nogueira et al., 2012
	Kidney	Inflammatory Kidney Disease w tubulointerstitial fibrosis	Nephrotoxic serum nephritis	Mouse	Pro-fibrotic	Pro-fibrotic: initiates nephritis through cell mediated events	Menke et al., 2008
	Liver	Hepatic fibrosis	carbon tetrachloride- induced	Mouse	Anti-fibrotic	Angiostatic and antifibrotic via modulation of stellate cell activation and endothelial cell inhibition. May or may not influence skewing of Th1-polarized, IFN-γ-positive cells in the liver.	Sahin et al., 2012, Wasmuth et al., 2009
		Liver cirrhosis	Spontaneous	Human	no direct effect shown	Low levels correlated with better survival following transjugular intrahepatic portosystemic shunt	Berres et al., 2015
		Hepatitis C Virus-associated fibrosis	Spontaneous	Human	dependent upon genotype	Alleles/polymorphisms of CXCL9/10/11 are associated with protection or promotion of fibrosis	Jiménez-Sousa et al., 2017, Pineda-Tenor et al., 2015
	Lung				?	not yet studied
	Pancreas	Chronic pancreatitis	Trinitrobenzene sulfonic acid (TNBS) induced	Rat	Anti-fibrotic	Attenuates fibrogenesis in vivo; has antifibrotic effects in vitro	Shen et al., 2013
	Skin	Morphea	Spontaneous	Human	Pro-fibrotic	Serum levels are correlated with disease activity	O'Brien et al., 2017; Mertens et al., 2018
	Multiorgan	Systemic scleroderma	Spontaneous	Human	no direct effect shown	Increased levels are documented in disease	Hasegawa et al., 2011; Liu et al., 2013; Rabquer et al., 2011
CXCL10	Heart	Chagas cardiomyopathy	Spontaneous; induced	Human; Beagle dog	no direct effect shown	Increased migration of inflammatory infiltrates to the heart; polymorphism CXCL10 rs3921 GG was associated with protection from progression to severe CCC	Nogueira et al., 2012
	Kidney	Inflammatory Kidney Disease	Nephrotoxic serum nephritis	Mouse	no direct effect shown	Not fully understood but seems to be dispensable for pathology	Menke et al., 2008
	Liver	Hepatic fibrosis	carbon tetrachloride- induced	Mouse	Pro-fibrotic	CXCL10 prevents NK cells from inactivating hepatic stellate cells	Hintermann et al., 2010
	Lung	Pulmonary fibrosis	Bleomycin induced	Mouse	Anti-fibrotic	Limits fibrosis by reducing fibroblast migration to lung tissue	Tager et al., 2004; Jiang et al., 2010
	Pancreas				?	not yet studied
	Skin	Morphea	Spontaneous	Human	no direct effect shown	Serum levels are correlated with disease activity	Mertens et al., 2018
	Multiorgan	Systemic scleroderma	Spontaneous	Human	no direct effect shown	Increased levels are documented in disease	Hasegawa et al., 2011; Liu et al., 2013; Rabquer et al., 2011
CXCL11	Lung	Pulmonary Fibrosis	Bleomycin induced	Mouse	Anti-fibrotic	Systemic CXCL11 administration reduced pulmonary collagen deposition, procollagen gene expression, and histopathologic fibroplasia and extracellular matrix deposition in the lung. CXCR3 is not expressed on fibroblasts; CXCL11 had no direct effect on pulmonary fibroblasts.	Burdick et al., 2005
		Systemic scleroderma	Spontaneous	Human	no direct effect shown	High bronchoalveolar lavage fluid CXCL11 correlates with less risk of developing interstitial lung disease	Cardarelli et al., 2012
CXCL4 (binds CXCR3-B)	Liver	Hepatic fibrosis	carbon tetrachloride- induced	Mouse	no direct effect shown	Angiostatic: Directly interrupts VEGF signaling	Sulpice et al., 2004

Table 1 Complete References:

1. Lin C-F, Su C-J, Liu J-H, Chen S-T, Huang H-L, Pan S-L. Potential Effects of CXCL9 and CCL20 on Cardiac Fibrosis in Patients with Myocardial Infarction and Isoproterenol-Treated Rats. J Clin Med Res [Internet]. 2019 May 11;8(5). Available from: http://dx.doi.org/10.3390/jcm8050659

2. Faé KC, Palacios SA, Nogueira LG, Oshiro SE, Demarchi LMF, Bilate AMB, et al. CXCL9/Mig mediates T cells recruitment to valvular tissue lesions of chronic rheumatic heart disease patients. Inflammation [Internet]. 2013 Aug;36(4):800–11. Available from: http://dx.doi.org/10.1007/s10753-013-9606-2

3. Nogueira LG, Santos RHB, Ianni BM, Fiorelli AI, Mairena EC, Benvenuti LA, et al. Myocardial chemokine expression and intensity of myocarditis in Chagas cardiomyopathy are controlled by polymorphisms in CXCL9 and CXCL10. PLoS Negl Trop Dis [Internet]. 2012 Oct 25;6(10):e1867. Available from: http://dx.doi.org/10.1371/journal.pntd.0001867

4. Menke J, Zeller GC, Kikawada E, Means TK, Huang XR, Lan HY, et al. CXCL9, but not CXCL10, promotes CXCR3-dependent immune-mediated kidney disease. J Am Soc Nephrol [Internet]. 2008 Jun;19(6):1177–89. Available from: http://dx.doi.org/10.1681/ASN.2007111179

5. Sahin H, Borkham-Kamphorst E, Kuppe C, Zaldivar MM, Grouls C, Al-samman M, et al. Chemokine Cxcl9 attenuates liver fibrosis-associated angiogenesis in mice. Hepatology [Internet]. 2012 May 19;55(5):1610–9. Available from: http://doi.wiley.com/10.1002/hep.25545

6. Pineda-Tenor D, Berenguer J, García-Álvarez M, Guzmán-Fulgencio M, Carrero A, Aldámiz-Echevarria T, et al. Single Nucleotide Polymorphisms of CXCL9-11 Chemokines Are Associated With Liver Fibrosis in HIV/HCV-Coinfected Patients. JAIDS Journal of Acquired Immune Deficiency Syndromes [Internet]. 2015 Apr 1 [cited 2020 Sep 23];68(4):386. Available from: https://journals.lww.com/jaids/fulltext/2015/04010/Single_Nucleotide_Polymorphisms_of_CXCL9_11.3.aspx?casa_token=2kMFCv_y5KcAAAAA:HJXjuc13C4IdQ0jXRz84X8bBYfKwrt3RWyPB1FpyLCOBTq2l4yTRsbYdS8OG9T0O0-hh-nBzVTb-_you33IXjJo

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8. Wasmuth HE, Lammert F, Zaldivar MM, Weiskirchen R, Hellerbrand C, Scholten D, et al. Antifibrotic effects of CXCL9 and its receptor CXCR3 in livers of mice and humans. Gastroenterology [Internet]. 2009 Jul;137(1):309–19, 319.e1–3. Available from: http://dx.doi.org/10.1053/j.gastro.2009.03.053

9. Berres M-L, Asmacher S, Lehmann J, Jansen C, Görtzen J, Klein S, et al. CXCL9 is a prognostic marker in patients with liver cirrhosis receiving transjugular intrahepatic portosystemic shunt. J Hepatol [Internet]. 2015 Feb;62(2):332–9. Available from: http://dx.doi.org/10.1016/j.jhep.2014.09.032

10. Shen J, Gao J, Chen C, Lu H, Hu G, Shen J, et al. Antifibrotic role of chemokine CXCL9 in experimental chronic pancreatitis induced by trinitrobenzene sulfonic acid in rats. Cytokine [Internet]. 2013 Oct;64(1):382–94. Available from: http://dx.doi.org/10.1016/j.cyto.2013.05.012

11. O’Brien JC, Rainwater YB, Malviya N, Cyrus N, Auer-Hackenberg L, Hynan LS, et al. Transcriptional and Cytokine Profiles Identify CXCL9 as a Biomarker of Disease Activity in Morphea. J Invest Dermatol [Internet]. 2017 Aug;137(8):1663–70. Available from: http://dx.doi.org/10.1016/j.jid.2017.04.008

12. Mertens JS, de Jong EMGJ, Pandit A, Seyger MMB, Hoppenreijs EPAH, Thurlings RM, et al. Regarding “Transcriptional and Cytokine Profiles Identify CXCL9 as a Biomarker of Disease Activity in Morphea.” J Invest Dermatol [Internet]. ncbi.nlm.nih.gov; 2018 May;138(5):1212–5. Available from: http://dx.doi.org/10.1016/j.jid.2017.11.032

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14. Rabquer BJ, Tsou P-S, Hou Y, Thirunavukkarasu E, Haines GK 3rd, Impens AJ, et al. Dysregulated expression of MIG/CXCL9, IP-10/CXCL10 and CXCL16 and their receptors in systemic sclerosis. Arthritis Res Ther [Internet]. 2011 Feb 8;13(1):R18. Available from: http://dx.doi.org/10.1186/ar3242

15. Liu X, Mayes MD, Tan FK, Wu M, Reveille JD, Harper BE, et al. Correlation of interferon-inducible chemokine plasma levels with disease severity in systemic sclerosis. Arthritis & Rheumatism [Internet]. 2013;65(1):226–35. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1002/art.37742

16. Hintermann E, Bayer M, Pfeilschifter JM, Luster AD, Christen U. CXCL10 promotes liver fibrosis by prevention of NK cell mediated hepatic stellate cell inactivation. J Autoimmun [Internet]. 2010 Dec;35(4):424–35. Available from: http://dx.doi.org/10.1016/j.jaut.2010.09.003

17. Tager AM, Kradin RL, LaCamera P, Bercury SD, Campanella GSV, Leary CP, et al. Inhibition of pulmonary fibrosis by the chemokine IP-10/CXCL10. Am J Respir Cell Mol Biol [Internet]. 2004 Oct;31(4):395–404. Available from: http://dx.doi.org/10.1165/rcmb.2004-0175OC

18. Jiang D, Liang J, Campanella GS, Guo R, Yu S, Xie T, et al. Inhibition of pulmonary fibrosis in mice by CXCL10 requires glycosaminoglycan binding and syndecan-4. J Clin Invest [Internet]. 2010 Jun;120(6):2049–57. Available from: http://dx.doi.org/10.1172/JCI38644

19. Cardarelli S, Facco M, Fittà C, Del Rosso A. CXCL11 in bronchoalveolar lavage fluid and pulmonary function decline in systemic sclerosis. Clinical and [Internet]. 2012; Available from: https://www.academia.edu/download/45798612/CXCL11_in_bronchoalveolar_lavage_fluid_a20160520-15769-1pwsbty.pdf

20. Burdick MD, Murray LA, Keane MP, Xue YY, Zisman DA, Belperio JA, et al. CXCL11 attenuates bleomycin-induced pulmonary fibrosis via inhibition of vascular remodeling. Am J Respir Crit Care Med [Internet]. 2005 Feb 1;171(3):261–8. Available from: http://dx.doi.org/10.1164/rccm.200409-1164OC

21. Sulpice E, Contreres J-O, Lacour J, Bryckaert M, Tobelem G. Platelet factor 4 disrupts the intracellular signalling cascade induced by vascular endothelial growth factor by both KDR dependent and independent mechanisms. Eur J Biochem [Internet]. 2004 Aug;271(16):3310–8. Available from: http://dx.doi.org/10.1111/j.1432-1033.2004.04263.x