Neurological Sciences

, Volume 40, Issue 4, pp 779–791 | Cite as

Protective effects of CX3CR1 on autoimmune inflammation in a chronic EAE model for MS through modulation of antigen-presenting cell-related molecular MHC-II and its regulators

  • Weihua MaiEmail author
  • Xingwei Liu
  • Junfeng Wang
  • Jing Zheng
  • Xiao Wang
  • Wenying Zhou
Original Article



Recent evidences have implicated neuroprotective effects of CX3CR1 in multiple sclerosis (MS). But whether CX3CR1 is involved in modulation of antigen-presenting cell (APC)–related molecular MHC-II and what the possible mechanism is remain unidentified.


In this study, we intended to investigate the effects of CX3CR1 on MHC-II expressions on brain myeloid cells in experimental autoimmune encephalomyelitis (EAE) mice and explore the possible regulators for it.


CX3CR1-deficient EAE mice were created. Disease severity, pathological damage, and the expressions of MHC-II and its mediators on myeloid cells were detected.


We found that compare with wile-typed EAE mice, CX3CR1-deficient EAE mice exhibited more severe disease severity. An accumulation of CD45+CD115+Ly6CCD11c+ cells was reserved in the affected EAE brain of CX3CR1-deficient mice, consistent with disease severity and pathological damage in the brain. The expressions of MHC-II on the brain CD45+CD115+Ly6CCD11c+ cells of CX3CR1-deficient EAE mice were elevated, in accord with the increased protein and mRNA expressions of class II transactivator (CIITA) and interferon regulatory factor-1 (IRF-1).


The findings indicated that CX3CR1 might be an important regulator for MHC-II expressions on APCs, playing a beneficial role in EAE. The mechanism was probably through regulation on the MHC-II regulators CIITA and IRF-1.


Multiple sclerosis Experimental autoimmune encephalomyelitis CX3CR1 Major histocompatibility complex class II molecules Class II transactivator Interferon regulatory factor-1 


Funding information

This work was supported by the Natural Science Foundation of Guangdong Province, China (Grant No: 2014A030313028), and Science and Technology Planning Project of Zhuhai city, China (Grant No: 2015A1011).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Serbina NV, Pamer EG (2006) Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nat Immunol 7:311–317CrossRefGoogle Scholar
  2. 2.
    Auffray C, Sieweke M, Geissmann F (2009) Blood monocytes: development, heterogeneity, and relationship with dendritic cells. Annu Rev Immunol 27:669–692CrossRefGoogle Scholar
  3. 3.
    Cardona AE, Pioro EP, Sasse ME, Kostenko V, Cardona SM, Dijkstra IM, Huang D, Kidd G, Dombrowski S, Dutta R, Lee JC, Cook DN, Jung S, Lira SA, Littman DR, Ransohoff RM (2006) Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci 9:917–924CrossRefGoogle Scholar
  4. 4.
    Hatori K, Nagai A, Heisel R, Ryu JK, Kim SU (2002) Fractalkine and fractalkine receptors in human neurons and glial cells. J Neurosci Res 69:418–426CrossRefGoogle Scholar
  5. 5.
    Tuo J, Smith BC, Bojanowski CM, Meleth AD, Gery I, Csaky KG, Chew EY, Chan CC (2004) The involvement of sequence variation and expression of CX3CR1 in the pathogenesis of age-related macular degeneration. FASEB J 18:1297–1299CrossRefGoogle Scholar
  6. 6.
    Chan CC, Tuo J, Bojanowski CM, Csaky KG, Green WR (2005) Detection of CX3CR1 single nucleotide polymorphism and expression on archived eyes with age-related macular degeneration. Histol Histopathol 20:857–863Google Scholar
  7. 7.
    Meucci O, Fatatis A, Simen AA, Miller RJ (2000) Expression of CX3CR1 chemokine receptors on neurons and their role in neuronal survival. Proc Natl Acad Sci U S A 97:8075–8080CrossRefGoogle Scholar
  8. 8.
    Lauro C, Di Angelantonio S, Cipriani R, Sobrero F, Antonilli L, Brusadin V, Ragozzino D, Limatola C (2008) Activity of adenosine receptors type 1 is required for CX3CL1-mediated neuroprotection and neuromodulation in hippocampal neurons. J Immunol 180:7590–7596CrossRefGoogle Scholar
  9. 9.
    Lauro C, Cipriani R, Catalano M, Trettel F, Chece G, Brusadin V, Antonilli L, van Rooijen N, Eusebi F, Fredholm BB, Limatola C (2010) Adenosine A1 receptors and microglial cells mediate CX3CL1-induced protection of hippocampal neurons against Glu-induced death. Neuropsychopharmacology 35:1550–1559CrossRefGoogle Scholar
  10. 10.
    Garcia JA, Pino PA, Mizutani M, Cardona SM, Charo IF, Ransohoff RM, Forsthuber TG, Cardona AE (2013) Regulation of adaptive immunity by the fractalkine receptor during autoimmune inflammation. J Immunol 191:1063–1072CrossRefGoogle Scholar
  11. 11.
    Stojković L, Djurić T, Stanković A, Dinčić E, Stančić O, Veljković N, Alavantić D, Zivković M (2012) The association of V249I and T280M fractalkine receptor haplotypes with disease course of multiple sclerosis. J Neuroimmunol 245:87–92CrossRefGoogle Scholar
  12. 12.
    Huang D, Shi FD, Jung S, Pien GC, Wang J, Salazar-Mather TP, He TT, Weaver JT, Ljunggren HG, Biron CA, Littman DR, Ransohoff RM (2006) The neuronal chemokine CX3CL1/fractalkine selectively recruits NK cells that modify experimental autoimmune encephalomyelitis within the central nervous system. FASEB J 20:896–905CrossRefGoogle Scholar
  13. 13.
    De Keyser J, Laureys G, Demol F, Wilczak N, Mostert J, Clinckers R (2010) Astrocytes as potential targets to suppress inflammatory demyelinating lesions in multiple sclerosis. Neurochem Int 57:446–450CrossRefGoogle Scholar
  14. 14.
    Jung S, Aliberti J, Graemmel P, Sunshine MJ, Kreutzberg GW, Sher A, Littman DR (2000) Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol Cell Biol 20:4106–4114CrossRefGoogle Scholar
  15. 15.
    Pluchino S, Quattrini A, Brambilla E, Gritti A, Salani G, Dina G, Galli R, Del Carro U, Amadio S, Bergami A, Furlan R, Comi G, Vescovi AL, Martino G (2003) Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis. Nature 422:688–694CrossRefGoogle Scholar
  16. 16.
    Ridderstad Wollberg A, Ericsson-Dahlstrand A, Juréus A, Ekerot P, Simon S, Nilsson M, Wiklund SJ, Berg AL, Ferm M, Sunnemark D, Johansson R (2014) Pharmacological inhibition of the chemokine receptor CX3CR1 attenuates disease in a chronic-relapsing rat model for multiple sclerosis. Proc Natl Acad Sci U S A 111:5409–5414CrossRefGoogle Scholar
  17. 17.
    Geissmann F, Manz MG, Jung S, Sieweke MH, Merad M, Ley K (2010) Development of monocytes, macrophages, and dendritic cells. Science 327:656–661CrossRefGoogle Scholar
  18. 18.
    Geissmann F, Jung S, Littman DR (2003) Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19:71–82CrossRefGoogle Scholar
  19. 19.
    Saederup N, Cardona AE, Croft K, Mizutani M, Cotleur AC, Tsou CL, Ransohoff RM, Charo IF (2010) Selective chemokine receptor usage by central nervous system myeloid cells in CCR2-red fluorescent protein knock-in mice. PLoS One 5:e13693CrossRefGoogle Scholar
  20. 20.
    Platt AM, Mowat AM (2008) Mucosal macrophages and the regulation of immune responses in the intestine. Immunol Lett 119:22–31CrossRefGoogle Scholar
  21. 21.
    Bellavance MA, Gosselin D, Yong VW, Stys PK, Rivest S (2015) Patrolling monocytes play a critical role in CX3CR1-mediated neuroprotection during excitotoxicity. Brain Struct Funct 220:1759–1776CrossRefGoogle Scholar
  22. 22.
    Harton JA, Ting JP (2000) Class II transactivator: mastering the art of major histocompatibility complex expression. Mol Cell Biol 20:6185–6194CrossRefGoogle Scholar
  23. 23.
    Moreno CS, Beresford GW, Louis-Plence P, Morris AC, Boss JM (1999) CREB regulates MHC class II expression in a CIITA-dependent manner. Immunity 10:143–151CrossRefGoogle Scholar
  24. 24.
    Nikodemova M, Watters JJ, Jackson SJ, Yang SK, Duncan ID (2007) Minocycline down-regulates MHC II expression in microglia and macrophages through inhibition of IRF-1 and protein kinase C (PKC) alpha/beta II. J Biol Chem 282:15208–15216CrossRefGoogle Scholar
  25. 25.
    Barbaro Ade L, Tosi G, Frumento G, Bruschi E, D'Agostino A, Valle MT, Manca F, Accolla RS (2002) Block of Stat-1 activation in macrophages phagocytosing bacteria causes reduced transcription of CIITA and consequent impaired antigen presentation. Eur J Immunol 32:1309–1318CrossRefGoogle Scholar
  26. 26.
    Stickel N, Hanke K, Marschner D, Prinz G, Köhler M, Melchinger W, Pfeifer D, Schmitt-Graeff A, Brummer T, Heine A, Brossart P, Wolf D, von Bubnoff N, Finke J, Duyster J, Ferrara J, Salzer U, Zeiser R (2017) MicroRNA-146a reduces MHC-II expression via targeting JAK/STAT signaling in dendritic cells after stem cell transplantation. Leukemia 31:2732–2741CrossRefGoogle Scholar

Copyright information

© Fondazione Società Italiana di Neurologia 2019

Authors and Affiliations

  1. 1.Department of NeurologyThe Fifth Affiliated Hospital of Sun Yat-sen UniversityZhuhaiChina
  2. 2.Department of General SurgeryThe Fifth Affiliated Hospital of Sun Yat-sen UniversityZhuhaiChina
  3. 3.Department of NephrologyThe Fifth Affiliated Hospital of Sun Yat-sen UniversityZhuhaiChina
  4. 4.Department of Laboratory ScienceThe Fifth Affiliated Hospital of Sun Yat-sen UniversityZhuhaiChina

Personalised recommendations