CXCR3 chemokine receptor ligands in sarcoidosis

Sarcoidosis is a polysystemic inflammatory disease of unknown etiology, morphologically related to the group of granulomatosis, with heterogeneous clinical manifestations and outcomes. Immune cells, in particular T helper cells, are attracted to lung tissue and/or other organs by chemokine gradients and play an important role in the granuloma formation. T helper cells migrate from peripheral blood to the tissues due to expression of CXCR3 chemokine receptor on their surface. It interacts, e.g., with CXCL9/MIG, CXCL10/IP- 10, and CXCL11/I-TAC. Our study was aimed for determining the levels of CXCL9/MIG, CXCL10/IP-10, CXCL11/I-TAC chemokines in peripheral blood of the patients with sarcoidosis, depending on the features of their clinical course before administration of immunosuppressive therapy. We studied peripheral blood plasma samples of the patients with sarcoidosis (n = 52). In 37% (19/52), they exhibited acute clinical manifestations, and 63% (33/52) had chronic sarcoidosis. The control group included peripheral blood samples from healthy volunteers (n = 22). The chemokine concentrations (pg/ml) were determined by multiplex analysis using xMAP technology (Luminex), and Milliplex MAP test system (Millipore, USA). In the patients with sarcoidosis, significantly higher levels of chemokines were shown relative to healthy volunteers: CXCL9, 4013.00 pg/ml vs 1142.00 pg/ml (p < 0.001); CXCL10, 565.90 pg/ml vs 196.60 pg/ml (p < 0.001); CXCL11, 230.20 pg/ml vs 121.10 pg/ml (p = 0.018). Plasma concentrations of CXCL9 and CXCL10 were significantly increased both in blood samples from patients with acute and chronic sarcoidosis compared to healthy volunteers, p < 0.001. The level of CXCL11 chemokine was significantly increased only in the patients with chronic sarcoidosis, compared to the healthy volunteers: respectively, 251.50 pg/ml and 121.10 pg/ml (p = 0.044). The levels of this chemokine correlated with the activity of angiotensin-converting enzyme (ACE), with r = 0.374; p = 0.042. The ACE level in sarcoidosis is considered a clinical and laboratory index of the disease activity. In acute sarcoidosis, the level of CXCL11 chemokine was not significantly higher than in healthy individuals, whereas the CXCL9 chemokine content was significantly increased and correlated with ACE activity (r = 0.762; p = 0.037). The level of CXCL9 chemokine was significantly decreased in patients with signs of fibrosis as compared with fibrosis-free patients (1839.88 pg/ml vs 4375.52 pg/ml, p = 0.035). Significantly higher levels of CXCL9 were detected in cases of systemic sarcoidosis, i.e. 6036.84 pg/ml, as compared with 1927.44 pg/ml in the patients without these signs (p = 0.018). Evaluation of clinical and laboratory diagnostic characteristics for plasma chemokine levels in sarcoidosis patients allowed to assess their sensitivity and specificity. The respective values were as follows: in acute sarcoidosis: for CXCL9, 84% and 95%; for CXCL10, 84% and 95%; for CXCL11, 74% and 59%. In chronic sarcoidosis, the respective values for CXCL9 were 82% and 72%; for CXCL10, 91% and 77%; for CXCL11, 79% and 55%, respectively. Thus, the determination of plasma CXCL9, CXCL10, and CXCL11 chemokines in sarcoidosis allows of understanding their role in development of the disease, e.g., recruitment of T helper cells from peripheral blood to the lung tissue, and granuloma formation. Clinical and immunological comparisons of CXCL9 levels in the peripheral blood of patients and characteristics of the clinical course of sarcoidosis indicate to the role of this diagnostic parameter for assessing the disease activity, signs of lung fibrosis, and systemic manifestations in this disease.

1. Arsentieva N.A., Semenov A.V., Zhebrun D.A., Vasilyeva E.V., Totolian A.A. Role of CXCR3 chemokine receptor and its ligands in certain diseases. Meditsinskaya immunologiya = Medical Immunology (Russia), 2019, Vol. 21, no. 4, pp. 617-632. (In Russ.) doi: 10.15789/1563-0625-2019-4-617-632.

2. Baranova O.P., Kudryavtsev I.V., Lazareva N.M., Serebriakova M.K., Ses’ T.P., Ilkovich M.M., Totolian Areg A. Cytotoxic T lymphocytes in chronic sarcoidosis. Rossiyskiy immunologicheskiy zhurnal = Russian Journal of Immunology, 2018, Vol. 12 (21), no. 4, pp. 605-608. (In Russ.)

3. Ilkovich M.M. Diffuse parenchymal lung diseases. Moscow: GEOTAR-Media, 2021. 440 p.

4. Kudryavtsev I.V., Borisov A.G., Krobinets I.I., Savchenko A.A., Serebryakova M.K., Totolyan A.A. Chemokine receptors at distinct differentiation stages of T-helpers from peripheral blood. Meditsinskaya immunologiya = Medical Immunology (Russia), 2016, Vol. 18, no. 3, pp. 239-250. (In Russ.) doi: 10.15789/1563-0625-2016-3-239-250.

5. Lazareva N.M., Kudryavtsev I.V., Baranova O.P., Serebriakova M.K., Ses’ T.P., Ilkovich M.M., Totolian Areg A. Peripheral blood cytotoxic T cells in patients with sarcoidosis. Rossiyskiy immunologicheskiy zhurnal = Russian Journal of Immunology, 2018, Vol. 12 (21), no. 3, pp. 348-353. (In Russ.)

6. Lazareva N.M., Kudryavtsev I.V., Baranova O.P., Serebriakova M.K., Ses’ T.P., Ilkovich M.M., Totolian Areg A. Peripheral blood B cell subsets from patients with various activity of chronic sarcoidosis. Meditsinskaya immunologiya = Medical Immunology (Russia), 2019, Vol. 21, no. 6, pp. 1081-1098. (In Russ.) doi: 10.15789/1563-0625-2019-6-1081-1098.

7. Lazareva N.M., Baranova O.P., Kudryavtsev I.V., Arsentieva N.A., Liubimova N.E., Ses’ T.P., Ilkovich M.M., Totolian Areg A. Features of cytokine profile in patients with sarcoidosis. Meditsinskaya immunologiya = Medical Immunology (Russia), 2020, Vol. 22, no. 5, pp. 993-1002. (In Russ.) doi: 10.15789/1563-0625-FOC-2064.

8. Aksoy M.O., Yang Y., Ji R., Reddy P.J., Shahabuddin S., Litvin J., Rogers T.J., Kelsen S.G. CXCR3 surface expression in human airway epithelial cells: cell cycle dependence and effect on cell proliferation. Am. J. Physiol. Lung Cell Mol. Physiol., 2006, Vol. 290, no. 5, pp. 909-918.

9. Antonelli A., Ferrari S.M., Frascerra S. et al. Increase of circulating CXCL9 and CXCL11 associated with euthyroid or subclinically hypothyroid autoimmune thyroiditis. J. Clin. Endocrinol. Metab., 2011, Vol. 96, pp. 1859-1863.

10. Antonelli A., Ferrari S.M., Frascerra S. et al. Circulating chemo-kine (CXC motif) ligand (CXCL) 9 is increased in aggressive chronic autoimmune thyroiditis, in association with CXCL10. Cytokine, 2011, Vol. 55, pp. 288-293.

11. Arger N.K., Ho M., Woodruff P.G., Koth L.L. Serum CXCL11 correlates with pulmonary outcomes and disease burden in sarcoidosis. Respir. Med., 2019, Vol. 152, pp. 89-96.

12. Arger N.K., Ho M.E., Allen I.E., Benn B.S., Woodruff P.G., Koth L.L. CXCL9 and CXCL10 are differentially associated with systemic organ involvement and pulmonary disease severity in sarcoidosis. Respir. Med., 2020, Vol. 161, 105822. doi: 10.1016/j.rmed.2019.105822.

13. Bertolini T.B., Piñeros A.R., Prado R.Q., Gembre A.F., Ramalho L.N.Z., Alves-Filho J.C., Bonato V.L.D. CCR4-dependent reduction in the number and suppressor function of CD4+Foxp3+ cells augments IFN-γ-mediated pulmonary inflammation and aggravates tuberculosis pathogenesis. Cell Death Dis., 2018, Vol. 10, no. 1, 11. doi: 10.1038/s41419-018-1240-3.

14. Broos C.E., van Nimwegen M., Hoogsteden H.C., Hendriks R.W., Kool M., van den Blink B. Granuloma formation in pulmonary sarcoidosis. Front. Immunol., 2013, Vol. 10, no. 4, 437. doi: 10.3389/fimmu.2013.00437.

15. Chappell A.G., Cheung W.Y., Hutchings H.A. Sarcoidosis: a long-term follow up study. Sarcoidosis Vasc. Diffuse. Lung. Dis., 2000, Vol. 17, no. 2, pp. 167-173.

16. Cole K.E., Strick C.A., Paradis T.J., Ogborne K.T., Loetscher M., Gladue R.P., Lin W., Boyd J.G., Moser B., Wood D.E., Sahagan B.G., Neote K. Interferoninducible T cell alpha chemoattractant (I-TAC): a novel non-ELR CXC chemokine with potent activity on activated T cells through selective high affinity binding to CXCR3. J. Exp. Med., 1998, Vol. 187, no. 12, pp. 2009-2021.

17. Colvin R.A., Campanella G.S., Sun J., Luster A.D. Intracellular domains of CXCR3 that mediate CXCL9, CXCL10, and CXCL11 function. J. Biol. Chem., 2004, Vol. 279, no. 29, pp. 30219-30227.

18. Cooke G., Govender P., Watson C.J., Armstrong M.E., O’Dwyer D.N., Keane M.P., King R., Tynan A., Dunn M., Donnelly S.C. Sarcoidosis, alveolar β-actin and pulmonary fibrosis. QJM, 2013, Vol. 106, no. 10, pp. 897-902.

19. Fallahi P., Ferri C., Ferrari S.M. et al. Cytokines and HCV-related disorders. Clin. Dev. Immunol., 2012, Vol. 2012, 468107. doi: 10.1155/2012/468107.

20. Garcia-Lopez M.A., Sanchez-Madrid F., Rodriguez-Frade J.M., Mellado M., Acevedo A., Garcia M.I., Albar J.P., Martinez C., Marazuela M. CXCR3 chemokine receptor distribution in normal and inflamed tissues: expression on activated lymphocytes, endothelial cells, and dendritic cells. Lab. Invest., 2001, Vol. 81, pp. 409-418.

21. Geyer A.I., Kraus T., Roberts M., Wisnivesky J., Eber C.D., Hiensch R., Moran T.M. Plasma level of interferon γ induced protein 10 is a marker of sarcoidosis disease activity. Cytokine, 2013, Vol. 64, no. 1, pp. 152-157.

22. Groom J.R., Luster A.D. CXCR3 ligands: redundant, collaborative and antagonistic functions. Immunol. Cell Biol., 2011, Vol. 89, no. 2, pp. 207-215.

23. Hunninghake G.W., Costabel U., Ando M., Baughman R., Cordier J.F., du Bois R., Eklund A., Kitaichi M., Lynch J., Rizzato G., Rose C., Selroos O., Semenzato G., Sharma O.P. ATS/ERS/WASOG statement on sarcoidosis. American thoracic society/European respiratory society/world association of sarcoidosis and other granulomatous disorders. Sarcoidosis Vasc. Diffuse. Lung. Dis., 1999, Vol. 16, no. 2, pp. 149-173.

24. Jiang D., Huang X., Geng J., Dong R., Li S., Liu Z., Wang C., Dai H. Pulmonary fibrosis ina mouse model of sarcoid granulomatosis induced by booster challenge with Propionibacterium acnes. Oncotarget, 2016, Vol. 7, no. 23, pp. 33703-33714.

25. Kishi J., Nishioka Y., Kuwahara T., Kakiuchi S., Azuma M., Aono Y., Makino H., Kinoshita K., Kishi M., Batmunkh R., Uehara H., Izumi K., Sone S. Blockade of Th1 chemokine receptors ameliorates pulmonary granulomatosis in mice. Eur. Respir. J., 2011, Vol. 38, no. 2, pp. 415-424.

26. Kriegova E., Fillerova R., Tomankova T., Hutyrova B., Mrazek F., Tichy T., Kolek V., du Bois R.M., Petrek M. T-helper cell type-1 transcription factor T-bet is upregulated in pulmonary sarcoidosis. Eur. Respir. J., 2011, Vol. 38, no. 5, pp. 1136-1144.

27. Lacotte S., Brun S., Muller S. et al. CXCR3, inflammation, and autoimmune diseases. Ann. N. Y. Acad. Sci., 2009, Vol. 1173, pp. 310-317.

28. Lasagni L., Francalanci M., Annunziato F., Lazzeri E., Giannini S., Cosmi L., Sagrinati C., Mazzinghi B., Orlando C., Maggi E., Marra F., Romagnani S., Serio M., Romagnani P. 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. J. Exp. Med., 2003, Vol. 197, pp. 1537-1549.

29. Lee E.Y., Lee Z.H., Song Y.W. The interaction between CXCL10 and cytokines in chronic inflammatory arthritis. Autoimmun. Rev., 2013, Vol. 12, pp. 554-557.

30. Medoff B.D., Wain J.C., Seung E., Jackobek R., Means T.K., Ginns L.C., Farber J.M., Luster A.D. CXCR3 and its ligands in a murine model of obliterative bronchiolitis: regulation and function. J. Immunol., 2006, Vol. 176, no. 11, pp. 7087-7095.

31. Mollers M., Aries S.P., Dromann D., Mascher B., Braun J., Dalhoff K. Intracellular cytokine repertoire in different T cell subsets from patients with sarcoidosis. Thorax, 2001, Vol. 56, no. 6, pp. 487-493.

32. Muehlinghaus G., Cigliano L., Huehn S., Peddinghaus A., Leyendeckers H., Hauser A.E. Regulation of CXCR3 and CXCR4 expression during terminal differentiation of memory B cells into plasma cells. Blood, 2005, Vol. 105, pp. 3965-3971.

33. Nishioka Y., Manabe K., Kishi J. et al. CXCL9 and 11 in patients with pulmonary sarcoidosis: a role of alveolar macrophages. Clin. Exp. Immunol., 2007, Vol. 149, pp. 317-326.

34. Nureki S., Miyazaki E., Ando M., Ueno T., Fukami T., Kumamoto T., Sugisaki K., Tsuda T. Circulating levels of both Th1 and Th2 chemokines are elevated in patients with sarcoidosis. Respir. Med., 2008, Vol. 102, no. 2, pp. 239-247.

35. Ohmori Y., Wyner L., Narumi S., Armstrong D., Stoler M., Hamilton T.A. Tumor necrosis factor-alpha induces cell type and tissue-specific expression of chemoattractant cytokines in vivo. Am. J. Pathol., 1993, Vol. 142, no. 3, pp. 861-870.

36. Piotrowski W.J., Młynarski W., Fendler W. et al. Chemokine receptor CXCR3 ligands in bronchoalveolar lavage fluid: associations with radiological pattern, clinical course, and prognosis in sarcoidosis. Pol. Arch. Med. Wewn., 2014, Vol. 124, pp. 395-402.

37. Prasse A., Georges C.G., Biller H., Hamm H., Matthys H., Luttmann W., Virchow J.C. Th1 cytokine pattern in sarcoidosis is expressed by bronchoalveolar CD4+ and CD8+ T cells. Clin. Exp. Immunol., 2000, Vol. 122, no. 2, pp. 241-248.

38. Proost P., Verpoest S., Van de Borne K., Schutyser E., Struyf S., Put W., Ronsse I., Grillet B., Opdenakker G., van Damme J. Synergistic induction of CXCL9 and CXCL11 by Toll-like receptor ligands and interferon-gamma in fibroblasts correlates with elevated levels of CXCR3 ligands in septic arthritis synovial fluids. J. Leukoc. Biol., Vol. 75, no. 5, pp. 777-784.

39. Proost P., Vynckier A.K., Mahieu F., Put W., Grillet B., Struyf S., Wuyts A., Opdenakker G., Van Damme J. Microbial Toll-like receptor ligands differentially regulate CXCL10/IP-10 expression in fibroblasts and mononuclear leukocytes in synergy with IFN-gamma and provide a mechanism for enhanced synovial chemokine levels in septic arthritis. Eur. J. Immunol., 2003, Vol. 33, no. 11, pp. 3146-3153.

40. Ragusa F. Sarcoidosis and Th1 chemokines. Clin Ter., 2015, Vol. 166, no. 1, pp. e72-e76.

41. Ragusa F. Sarcoidosis and the Th1 chemokine MIG. Clin Ter., 2018, Vol. 169, no. 6, pp. e308-e313.

42. Sakthivel P., Bruder D. Mechanism of granuloma formation in sarcoidosis. Curr. Opin. Hematol., 2017, Vol. 24, no. 1, pp. 59-65.

43. Smit M.J., Verdijk P., van der Raaij-Helmer E.M. et al. CXCR3-mediated chemotaxis of human T cells is regulated by a Gi- and phospholipase C-dependent pathway and not via activation of MEK/p44/p42 MAPK nor Akt/PI-3 kinase. Blood, 2003, Vol. 102, pp. 1959-1965.

44. Strieter R.M., Burdick M.D., Gomperts B.N., Belperio J.A., Keane M.P. CXC chemokines in angiogenesis. Cytokine Growth Factor Rev., 2005, Vol. 16, no. 6, pp. 593-609.

45. Su R., Nguyen M.L., Agarwal M.R., et al. Interferon-inducible chemokines reflect severity and progression in sarcoidosis. Respir. Res., 2013, Vol. 14, 121. doi: 10.1186/1465-9921-14-121.

46. Takeuchi M., Oh-I K., Suzuki J. et al. Elevated serum levels of CXCL9/monokine induced by interferon-gamma and CXCL10/interferon-gamma-inducible protein-10 in ocular sarcoidosis. Invest. Ophthalmol. Vis. Sci., 2006, Vol. 47, pp. 1063-1068.

47. Torraca V., Cui C., Boland R., Bebelman J.P., van der Sar A.M., Smit M.J., Siderius M., Spaink H.P., Meijer A.H. The CXCR3-CXCL11 signaling axis mediates macrophage recruitment and dissemination of mycobacterial infection. Dis. Model. Mech., 2015, Vol. 8, no. 3, pp. 253-269.

48. van Raemdonck K., van den Steen P.E., Liekens S., van Damme J., Struyf S. CXCR3 ligands in disease and therapy. Cytokine Growth Factor Rev., 2015, Vol. 26, no. 3, pp. 311-327.

49. Xanthou G., Duchesnes C.E., Williams T.J., Pease J.E. CCR3 functional responses are regulated by both CXCR3 and its ligands CXCL9, CXCL10 and CXCL11. Eur. J. Immunol., 2003, Vol. 33, no. 8, pp. 2241-2250.