Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
JCR Impact Factor (IF) – 2.1
5-Year Impact Factor – 2.2
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Index Copernicus  – 161.11; MEiN – 140 pts

ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
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Advances in Clinical and Experimental Medicine

2018, vol. 27, nr 6, June, p. 849–856

doi: 10.17219/acem/68846

Publication type: review article

Language: English

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CXCL9, CXCL10, CXCL11, and their receptor (CXCR3) in neuroinflammation and neurodegeneration

Olga M. Koper1,A,B,C,D,F, Joanna Kamińska1,B,C,E,F, Karol Sawicki2,C,E,F, Halina Kemona1,E,F

1 Department of Clinical Laboratory Diagnostics, Medical University of Bialystok, Poland

2 Department of Neurosurgery, Medical Clinical Hospital in Bialystok, Poland


The aim of this review is to present data from the available literature concerning CXCL9, CXCL10 and CXCL11, as well as their receptor 3 (CXCR3) in selected diseases of the central nervous system (CNS), such as tickborne encephalitis (TBE), neuroborreliosis (NB), Alzheimer’s disease (AD), and multiple sclerosis (MS). CXCL9, CXCL10, and CXCL11 lack glutamic acid-leucine-arginine (ELR), and are unique, because they are more closely related to each other than to any other chemokine. The aforementioned chemokines are especially involved in Th1-type response and in various diseases, as their expression correlates with the tissue infiltration of T cells. Their production is strongly induced by interferon gamma (IFN-Υ), the most typical Th1 cytokine. They act by binding to the CXC3 receptor. Knowledge about the action mechanism of CXCR3 and its ligands may be useful in the treatment of CNS diseases. However, data in the literature concerning the evaluation of CXCL9, CXCL10, CXCL11, and their receptor with the use of the enzyme-linked immunosorbent assay (ELISA) method is limited.

Key words

chemokines, neurodegeneration, neuroinflammation, CXCR3

References (41)

  1. Mazur G, Jaskuła E, Kryczek I, et al. Proinflammatory chemokine gene expression influences survival of patients with non-Hodgkin’s lymphoma. Folia Histochem Cytobiol. 2011;49(2):240–247.
  2. Banisadr G, Rostène W, Kitabgi P, Parsadaniantz SM. Chemokines and brain functions. Curr Drug Targets Inflamm Allergy. 2005;4(3):387–399.
  3. Müller M, Carter S, Hofer MJ, Campbell IL. Review: The chemokine receptor CXCR3 and its ligands CXCL9, CXCL10, and CXCL11 in neuroimmunity – a tale of conflict and conundrum. Neuropathol Appl Neurobiol. 2010;36(5):368–387.
  4. Ramesh G, MacLean AG, Philipp MT. Cytokines and chemokines at the crossroads of neuroinflammation, neurodegeneration, and neuropathic pain. Mediators Inflamm. 2013:480739.
  5. Clark-Lewis I, Mattioli I, Gong JH, Loetscher P. Structure-function relationship between the human chemokine receptor CXCR3 and its ligands. J Biol Chem. 2003;278(1):289–295.
  6. Lazzeri E, Romagnani P. CXCR3-binding chemokines: Novel multifunctional therapeutic targets. Curr Drug Targets Immune Endocr Metabol Disord. 2005;5(1):109–118.
  7. Bajetto A, Bonavia R, Barbero S, Florio T, Schettini G. Chemokines and their receptors in the central nervous system. Front Neuroendocrinol. 2001;22(3):147–184.
  8. Bendall L. Chemokines and their receptors in disease. Histol Histopathol. 2005;20:907–926.
  9. Sorce S, Myburgh R, Krause KH. The chemokine receptor CCR5 in the central nervous system. Prog Neurobiol. 2011;93(2):297–311.
  10. Fernandez EJ, Lolis E. Structure, function, and inhibition of chemokines. Annu Rev Pharmacol Toxicol. 2002;42:469–499.
  11. Xia MQ, Bacskai BJ, Knowles RB, Qin SX, Hyman BT. Expression of the chemokine receptor CXCR3 on neurons and the elevated expression of its ligand IP-10 in reactive astrocytes: In vitro ERK1/2 activation and role in Alzheimer’s disease. J Neuroimmunol. 2000;108(1–2):227–235.
  12. Zlotnik A, Yoshie O. Chemokines: A new classification system and their role in immunity. Immunity. 2000;12(2):121–127.
  13. Li H, Gang Z, Yuling H, et al. Different neurotropic pathogens elicit neurotoxic CCR9- or neurosupportive CXCR3-expressing microglia. J Immunol. 2006;177(6):3644–3656.
  14. Loetscher M, Loetscher P, Brass N, Meese E, Moser B. Lymphocyte-specific chemokine receptor CXCR3: Regulation, chemokine binding and gene localization. Eur J Immunol. 1998;28(11):3696–3705.
  15. Fulton AM. The chemokine receptors CXCR4 and CXCR3 in cancer. Curr Oncol Rep. 2009;11(2):125–131.
  16. Lasagni L, Francalanci M, Annunziato F, et al. 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;197(11):1537–1549.
  17. Herpe B, Schuffenecker I, Pillot J, et al. Tick-borne encephalitis, southwestern France. Emerg Infect Dis. 2007;13(7):1114–1117.
  18. Bormane A, Lucenko I, Duks A, et al. Vectors of tick-borne diseases and epidemiological situation in Latvia in 1993–2002. Int J Med Microbiol. 2004;293(37):36–47.
  19. Holub M, Klucková Z, Beran O, Aster V, Lobovská A. Lymphocyte subset numbers in cerebrospinal fluid: Comparison of tick-borne encephalitis and neuroborreliosis. Acta Neurol Scand. 2002;106(5):302–308.
  20. Zajkowska J, Moniuszko-Malinowska A, Pancewicz SA, et al. Evaluation of CXCL10, CXCL11, CXCL12 and CXCL13 chemokines in serum and cerebrospinal fluid in patients with tick borne encephalitis (TBE). Adv Med Sci. 2011;56(2):311–317.
  21. Koper OM, Kamińska J, Grygorczuk S, Zajkowska J, Kemona H. CXCL9 concentrations in cerebrospinal fluid and serum of patients with tick-borne encephalitis. Arch Med Sci. 2018;14(2):313–320.
  22. Hubálek Z. Epidemiology of Lyme borreliosis. Curr Probl Dermatol. 2009;37:31–50.
  23. Henningsson AJ, Malmvall BE, Ernerudh J, Matussek A, Forsberg P. Neuroborreliosis – an epidemiological, clinical and healthcare cost study from an endemic area in the south-east of Sweden. Clin Microbiol Infect. 2010;16(8):1245–1251.
  24. Lepej SZ, Rode OD, Jeren T, Vince A, Remenar A, Barsić B. Increased expression of CXCR3 and CCR5 on memory CD4+ T-cells migrating into the cerebrospinal fluid of patients with neuroborreliosis: The role of CXCL10 and CXCL11. J Neuroimmunol. 2005;163(1–2):128–134.
  25. Rupprecht TA, Koedel U, Muhlberger B, Wilske B, Fontana A, Pfister HW. CXCL11 is involved in leucocyte recruitment to the central nervous system in neuroborreliosis. J Neurol. 2005;252(7):820–823.
  26. Henningsson AJ, Tjernberg I, Malmvall BE, Forsberg P, Ernerudh J. Indications of Th1 and Th17 responses in cerebrospinal fluid from patients with Lyme neuroborreliosis: A large retrospective study. J Neuroinflammation. 2011;20:8–36.
  27. Moniuszko A, Czupryna P, Pancewicz S, et al. Evaluation of CXCL8, CXCL10, CXCL11, CXCL12 and CXCL13 in serum and cerebrospinal fluid of patients with neuroborreliosis. Immunol Lett. 2014;157(1–2):45–50.
  28. Galimberti D, Schoonenboom N, Scarpini E, Scheltens P; Dutch-Italian Alzheimer Research Group. Chemokines in serum and cerebrospinal fluid of Alzheimer’s disease patients. Ann Neurol. 2003;53(4):547–548.
  29. Galimberti D, Schoonenboom N, Scheltens P, et al. Intrathecal chemokine levels in Alzheimer disease and frontotemporal lobar degeneration. Neurology. 2006;66(1):146–147.
  30. Farfara D, Lifshitz V, Frenkel D. Neuroprotective and neurotoxic properties of glial cells in the pathogenesis of Alzheimer’s disease. J Cell Mol Med. 2008;12(3):762–780.
  31. Schwab C, McGeer PL. Inflammatory aspects of Alzheimer disease and other neurodegenerative disorders. J Alzheimers Dis. 2008;13:359–369.
  32. Sui Y, Stehno-Bittel L, Li S, et al. CXCL10-induced cell death in neurons: Role of calcium dysregulation. Eur J Neurosci. 2006;23(4):957–964.
  33. Corrêa JD, Starling D, Teixeira AL, Caramelli P, Silva TA. Chemokines in CSF of Alzheimer’s disease patients. Arq Neuropsiquiatr. 2011;69(3):455–459.
  34. Goldenberg MM. Multiple sclerosis review. P&T. 2012;37(3):175–184.
  35. O’Gorman C, Lin R, Stankovich J, Broadley SA. Modelling genetic susceptibility to multiple sclerosis with family data. Neuroepidemiology. 2013;40(1):1–12.
  36. Kułakowska A, Bartosik-Psujek H, Hożejowski R, Mitosek-Szewczyk K, Drozdowski W, Stelmasiak Z. Wybrane aspekty epidemiologiczne stwardnienia rozsianego w Polsce – wieloośrodkowe badanie pilotażowe. Neurol Neurochir Pol. 2010;44(5):443–452.
  37. Salmaggi A, Gelati M, Dufour A, et al. Expression and modulation of IFN-gamma-inducible chemokines (IP-10, Mig, and I-TAC) in human brain endothelium and astrocytes: Possible relevance for the immune invasion of the central nervous system and the pathogenesis of multiple sclerosis. J Interferon Cytokine Res. 2002;22(6):631–640.
  38. Mahad DJ, Howell SJ, Woodroofe MN. Expression of chemokines in the CSF and correlation with clinical disease activity in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2002;72(4):498–502.
  39. Simpson JE, Newcombe J, Cuzner ML, Woodroofe MN. Expression of the interferon-gamma-inducible chemokines IP-10 and Mig and their receptor, CXCR3, in multiple sclerosis lesions. Neuropathol Appl Neurobiol. 2000;26(2):133–142.
  40. Balashov KE, Rottman JB, Weiner HL, Hancock WW. CCR5(+) and CXCR3(+) T cells are increased in multiple sclerosis and their ligands MIP-1alpha and IP-10 are expressed in demyelinating brain lesions. Proc Natl Acad Sci USA. 1999;96(12):6873–6878.
  41. Sørensen TL, Sellebjerg F, Jensen CV, Strieter RM, Ransohoff RM. Chemokines CXCL10 and CCL2: Differential involvement in intrathecal inflammation in multiple sclerosis. Eur J Neurol. 2001;8(6):665–672.