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Differential roles of resident microglia and infiltrating monocytes in murine CNS autoimmunity

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Abstract

Macrophages can be of dual origin. Most tissue-resident macrophage compartments are generated before birth and subsequently maintain themselves independently from each other locally in healthy tissue. Under inflammatory conditions, these cells can however be complemented by macrophages derived from acute monocyte infiltrates. Due to the lack of suitable experimental systems, differential functional contributions of central nervous system (CNS)-resident microglia and monocyte-derived macrophages (MoMF) to CNS inflammation, such as experimental autoimmune encephalomyelitis (EAE), the mouse model of multiple sclerosis (MS), remain poorly understood. Here, we will review recent progress in this field that suggest distinct roles of microglia and MoMF in disease induction and progression, capitalizing on novel transgenic mouse models. The latter finding could have major implications for the rationale development of therapeutic approaches to the management of brain inflammation and MS therapy.

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References

  1. Holmoy T, Hestvik AL (2008) Multiple sclerosis: immunopathogenesis and controversies in defining the cause. Curr Opin Infect Dis 21(3):271–278

    Article  PubMed  Google Scholar 

  2. Lisak RP (2007) Neurodegenaretion in multiple sclerosis: defining the problem. Neurology 68(22):43–54

    Google Scholar 

  3. Flecher JM, Lalor SJ, Sweeney M, Tubridy N, Mills KH (2010) T cells in multiple sclerosis and experimental autoimmune encephalonyelitis. Clin Exp Immunol 162(1):1–11

    Article  CAS  Google Scholar 

  4. Croxford AL, Kurschus FC, Waisman A (2011) Mouse models for multiple sclerosis: historical facts and future implication. Biochim Biophys Acta 1812(2):177–183

    Article  CAS  PubMed  Google Scholar 

  5. Hemmer B, Archelos JJ, Hartung HP (2002) New concepts in the immunopathogenesis of multiple sclerosis. Nat Rev Neurosci 3(4):291–301

    Article  CAS  PubMed  Google Scholar 

  6. Mendel I, Kerlero de Rosbo N, Ben-Nun A (1995) A myelin oligodendrocyte glycoprotein peptide induces typical chronic experimental autoimmune encephalomyelitis in H-2b mice: fine specificity and T cell receptor V beta expression of encephalitogenic T cells. Eur J Immunol 25(7):1951–1959

    Article  CAS  PubMed  Google Scholar 

  7. Miller SD, McMahon EJ, Schreiner B, Bailey SL (2007) Antigen presentation in the CNS by myeloid dendritic cells drives progression of relapsing experimental autoimmune encephalomyelitis. Ann N Y Acad Sci 1103:179–191

    Article  CAS  PubMed  Google Scholar 

  8. Ranshoff R, Perry V (2009) Microglial physiology: unique stimuli, specialized responses. Annu Rev Immunol 27:119–145

    Article  CAS  Google Scholar 

  9. 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(11):4106–4114

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314–1318

    Article  CAS  PubMed  Google Scholar 

  11. Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, Littman DR, Dustin ML, Gan WB (2005) ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 8(6):752–758

    Article  CAS  PubMed  Google Scholar 

  12. Alliot F, Godin I, Pessac B (1999) Microglia derive from progenitors, originating from the yolk sac, and which proliferate in the brain. Brain Res Dev Brain Res 117(2):145–152

    Article  CAS  PubMed  Google Scholar 

  13. Ginhoux FM, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, Mehler MF, Conway SJ, Ng LG, Stanley ER (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330:841–845

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Schulz CE, Gomez Perdiguero E, Chorro L, Szabo-Rogers H, Cagnard N, Kierdorf K, Prinz M, Wu B, Jacobsen SE, Pollard JW et al (2012) A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336(6077):86–90

    Article  CAS  PubMed  Google Scholar 

  15. Kierdorf K, Erny D, Goldmann T, Sander V, Schulz C, Perdiguero EG, Wieghofer P, Heinrich A, Riemke P, Hölscher C, Müller DN, Luckow B, Brocker T, Debowski K, Fritz G, Opdenakker G, Diefenbach A, Biber K, Heikenwalder M, Geissmann F, Rosenbauer F, Prinz M (2013) Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nat Neurosci 16(3):273–280

    Article  CAS  PubMed  Google Scholar 

  16. Gomez Perdiguero E, Klapproth K, Schulz C, Busch K, Azzoni E, Crozet L, Garner H, Trouillet C, de Bruijn MF, Geissmann F, Rodewald HR (2015) Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 518(7540):547–551

    Article  PubMed  CAS  Google Scholar 

  17. Soza-Ried C, Hess I, Netuschil N, Schorpp M, Boehm T (2010) Essential role of c-myb in definitive hematopoiesis is evolutionarily conserved. Proc Natl Acad Sci U S A 107(40):17304–17308

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Fogg DK, Sibon C, Miled C, Jung S, Aucouturier P, Littman DR, Cumano A, Geissmann F (2006) A clonogenic bone marrow progenitor specific for macrophages and dendritic cells. Science 311(5757):83–87

    Article  CAS  PubMed  Google Scholar 

  19. Varol C, Landsman L, Fogg DK, Greenshtein L, Gildor B, Margalit R, Kalchenko V, Geissmann F, Jung S (2007) Monocytes give rise to mucosal, but not splenic, conventional dendritic cells. J Exp Med 204(1):171–180

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Hettinger J, Richards DM, Hansson J, Barra MM, Joschko AC, Krijgsveld J, Feuerer M (2013) Origin of monocytes and macrophages in a committed progenitor. Nat Immunol 14(8):821–830

    Article  CAS  PubMed  Google Scholar 

  21. Mildner A, Yona S, Jung S (2013) A close encounter of the third kind: monocyte-derived cells. Adv Immunol 120:69–103

    Article  CAS  PubMed  Google Scholar 

  22. Varol C, Vallon-Eberhard A, Elinav E, Aychek T, Shapira Y, Luche H, Fehling HJ, Hardt WD, Shakhar G, Jung S (2009) Intestinal lamina propria dendritic cell subsets have different origin and functions. Immunity 31(3):502–512

    Article  CAS  PubMed  Google Scholar 

  23. Bogunovic M, Ginhoux F, Helft J, Shang L, Hashimoto D, Greter M, Liu K, Jakubzick C, Ingersoll MA, Leboeuf M, Stanley ER, Nussenzweig M, Lira SA, Randolph GJ, Merad M (2009) Origin of the lamina propria dendritic cell network. Immunity 31(3):513–525

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Bain CC, Bravo-Blas A, Scott CL, Gomez Perdiguero E, Geissmann F, Henri S, Malissen B, Osborne LC, Artis D, Mowat AM (2014) Constant replenishment from circulating monocytes maintains the macrophage pool in the intestine of adult mice. Nat Immunol 15(10):929–937

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Molawi K, Wolf Y, Kandalla PK, Favret J, Hagemeyer N, Frenzel K, Pinto AR, Klapproth K, Henri S, Malissen B, Rodewald HR, Rosenthal NA, Bajenoff M, Prinz M, Jung S, Sieweke MH (2014) Progressive replacement of embryo-derived cardiac macrophages with age. J Exp Med 211(11):2151–2158

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Ajami B, Bennett JL, Krieger C, McNagny KM, Rossi FM (2011) Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nat Neurosci 14:1142–1149

    Article  CAS  PubMed  Google Scholar 

  27. Ziegler-Heitbrock HW, Passlick B, Flieger D (1988) The monoclonal antimonocyte antibody My4 stains B lymphocytes and two distinct monocyte subsets in human peripheral blood. Hybridoma 7(6):521–527

    Article  CAS  PubMed  Google Scholar 

  28. Geissmann F, Jung S, Littman DR (2003) Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19(1):71–82

    Article  CAS  PubMed  Google Scholar 

  29. Palframan RT, Jung S, Cheng G, Weninger W, Luo Y, Dorf M, Littman DR, Rollins BJ, Zweerink H, Rot A, von Andrian UH (2001) Inflammatory chemokine transport and presentation in HEV: a remote control mechanism for monocyte recruitment to lymph nodes in inflamed tissues. J Exp Med 194(9):1361–1373

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Yona S, Kim KW, Wolf Y, Mildner A, Varol D, Breker M, Strauss-Ayali D, Viukov S, Guilliams M, Misharin A, Hume DA, Perlman H, Malissen B, Zelzer E, Jung S (2013) Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38(1):79–91

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Auffray C, Fogg D, Garfa M, Elain G, Join-Lambert O, Kayal S, Sarnacki S, Cumano A, Lauvau G, Geissmann F (2007) Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science 317(5838):666–670

    Article  CAS  PubMed  Google Scholar 

  32. Serbina NV, Shi C, Pamer EG (2012) Monocyte-mediated immune defense against murine Listeria monocytogenes infection. Adv Immunol 113:119–134

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Segura E, Amigorena S (2013) Inflammatory dendritic cells in mice and humans. Trends Immunol 34(9):440–445

    Article  CAS  PubMed  Google Scholar 

  34. Domínguez PM, Ardavín C (2010) Differentiation and function of mouse monocyte-derived dendritic cells in steady state and inflammation. Immunol Rev 234(1):90–104

    Article  PubMed  Google Scholar 

  35. Russell DG, Cardona PJ, Kim MJ, Allain S, Altare F (2009) Foamy macrophages and the progression of the human tuberculosis granuloma. Nat Immunol 10(9):943–948

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Hoover DL, Nacy CA (1984) Macrophage activation to kill Leishmaniatropica: defective intracellular killing of amastigotes by macrophages elicited with sterile inflammatory agents. J Immunol 132(3):1487–1493

    CAS  PubMed  Google Scholar 

  37. Noy R, Pollard JW (2014) Tumor-associated macrophages: from mechanisms to therapy. Immunity 41(1):49–61

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Gautier EL, Shay T, Miller J, Greter M, Jakubzick C, Ivanov S, Helft J, Chow A, Elpek KG, Gordonov S, Mazloom AR, Ma'ayan A, Chua WJ, Hansen TH, Turley SJ, Merad M, Randolph GJ, Immunological Genome Consortium (2012) Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat Immunol 13(11):1118–1128

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Lavin Y, Winter D, Blecher-Gonen R, David E, Keren-Shaul H, Merad M, Jung S, Amit I (2014) Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 159(6):1312–1326

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Solomon JN, Lewis CA, Ajami B, Corbel SY, Rossi FM, Krieger C (2006) Origin and distribution of bone marrow-derived cells in the central nervous system in a mouse model of amyotrophic lateral sclerosis. Glia 53(7):744–753

    Article  PubMed  Google Scholar 

  41. Lewis CA, Solomon JN, Rossi FM, Krieger C (2009) Bone marrow-derived cells in the central nervous system of a mouse model of amyotrophic lateral sclerosis are associated with blood vessels and express CX(3)CR1. Glia 57(13):1410–1419

    Article  PubMed  Google Scholar 

  42. Boillée S, Yamanaka K, Lobsiger CS, Copeland NG, Jenkins NA, Kassiotis G, Kollias G, Cleveland DW (2006) Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312(5778):1389–13892

    Article  PubMed  CAS  Google Scholar 

  43. Vom Berg J, Prokop S, Miller KR, Obst J, Kälin RE, Lopategui-Cabezas I, Wegner A, Mair F, Schipke CG, Peters O, Winter Y, Becher B, Heppner FL (2012) Inhibition of IL-12/IL-23 signaling reduces Alzheimer's disease-like pathology and cognitive decline. Nat Med 18(12):1812–1819

    Article  CAS  PubMed  Google Scholar 

  44. Olah M, Amor S, Brouwer N, Vinet J, Eggen B, Biber K, Boddeke HW (2012) Identification of a microglia phenotype supportive of remyelination. Glia 60(2):306–321

    Article  PubMed  Google Scholar 

  45. Lampron A, Larochelle A, Laflamme N, Préfontaine P, Plante MM, Sánchez MG, Yong VW, Stys PK, Tremblay MÈ, Rivest S (2015) Inefficient clearance of myelin debris by microglia impairs remyelinating processes. J Exp Med 212(4):481–495

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Matsushima GK, Morell P (2001) The neurotoxicant, cuprizone, as a model to study demyelination and remyelination in the central nervous system. Brain Pathol 11(1):107–116

    Article  CAS  PubMed  Google Scholar 

  47. Mills CD, Kincaid K, Alt JM, Heilman MJ, Hill AM (2000) M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol 164(12):6166–6173

    Article  CAS  PubMed  Google Scholar 

  48. Mills CD (2012) M1 and M2 macrophages: oracles of health and disease. Crit Rev Immunol 32(6):463–488

    Article  CAS  PubMed  Google Scholar 

  49. Chiu IM, Morimoto ET, Goodarzi H, Liao JT, O'Keeffe S, Phatnani HP, Muratet M, Carroll MC, Levy S, Tavazoie S, Myers RM, Maniatis T (2013) A neurodegeneration-specific gene-expression signature of acutely isolated microglia from an amyotrophic lateral sclerosis mouse model. Cell Rep 4(2):385–401

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Xue J, Schmidt SV, Sander J, Draffehn A, Krebs W, Quester I, De Nardo D, Gohel TD, Emde M, Schmidleithner L, Ganesan H, Nino-Castro A, Mallmann MR, Labzin L, Theis H, Kraut M, Beyer M, Latz E, Freeman TC, Ulas T, Schultze JL (2014) Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity 40(2):274–288

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Marik C, Felts PA, Bauer J, Lassmann H, Smith KJ (2007) Lesion genesis in a subset of patients with multiple sclerosis: a role for innate immunity? Brain 130(11):2800–2815

    Article  PubMed Central  PubMed  Google Scholar 

  52. Bhasin M, Wu M, Tsirka SE (2007) Modulation of microglial/macrophage activation by macrophage inhibitory factor (TKP) or tuftsin (TKPR) attenuates the disease course of experimental autoimmune encephalomyelitis. BMC Immunol 8:10

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  53. Ellrichmann G, Thöne J, Lee DH, Rupec RA, Gold R, Linker RA (2012) Constitutive activity of NF-kappa B in myeloid cells drives pathogenicity of monocytes and macrophages during autoimmune neuroinflammation. J Neuroinflammation 9:15

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Heppner FL, Greter M, Marino D, Falsig J, Raivich G, Hövelmeyer N, Waisman A, Rülicke T, Prinz M, Priller J, Becher B, Aguzzi A (2005) Experimental autoimmune encephalomyelitis repressed by microglial paralysis. Nat Med 11(2):146–152

    Article  CAS  PubMed  Google Scholar 

  55. Goldmann T, Wieghofer P, Muller P, Wolf W, Varol D, Yona S, Brendecke S, Kierdorf K, Staszewski O, Datta M, Luedde T, Hiekenwalder M, Jung S, Prinz M (2013) A new type of microglia gene targeting shows TAK1 to be pivotal in CNS autoimmune inflammation. Nat Neurosci 16(11):1618–1626

    Article  CAS  PubMed  Google Scholar 

  56. Sato S, Sanjo H, Takeda K, Ninomiya-Tsuji J, Yamamoto M, Kawai T, Matsumoto K, Takeuchi O, Akira S (2005) Essential function for the kinase TAK1 in innate and adaptive immune responses. Nat Immunol 6(11):1087–1095

    Article  CAS  PubMed  Google Scholar 

  57. Yamasaki R, Lu H, Butovsky O, Ohno N, Rietsch AM, Cialic R, Wu PM, Doykan CE, Lin J, Cotleur AC, Kidd G, Zorlu MM, Sun N, Hu W, Liu L, Lee JC, Taylor SE, Uehlein L, Dixon D, Gu J, Floruta CM, Zhu M, Charo IF, Weiner HL, Ransohoff RM (2014) Differential roles of microglia and monocytes in the inflamed central nervous system. J Exp Med 211(8):1533–1549

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Jiang Z, Jiang JX, Zhang GX (2014) Macrophages: a double-edged sword in experimental autoimmune encephalomyelitis. Immunol Lett 160(1):17–22

    Article  CAS  PubMed  Google Scholar 

  59. Takahashi K, Prinz M, Stagi M, Chechneva O, Neumann H (2007) TREM2-transduced myeloid precursors mediate nervous tissue debris clearance and facilitate recovery in an animal model of multiple sclerosis. PLoS Med 4(4), e124

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  60. 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(10), e13693

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  61. Shechter R, London A, Varol C, Raposo C, Cusimano M, Yovel G, Rolls A, Mack M, Pluchino S, Martino G, Jung S, Schwartz M (2009) Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice. PLoS Med 6(7), e1000113

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  62. McMahon EJ, Bailey SL, Castenada CV, Waldner S, Miller SD (2005) Epitope spreading initiates in the CNS in two mouse models of multiple sclerosis. Nat Med 11(3):335–339

    Article  CAS  PubMed  Google Scholar 

  63. Greter M, Heppner FL, Lemos MP, Odermatt BM, Goebels N, Laufer T, Noelle RJ, Becher B (2005) Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis. Nat Med 11(3):328–334

    Article  CAS  PubMed  Google Scholar 

  64. Wu GF, Shindler KS, Allenspach EJ, Stephen TL, Thomas HL, Mikesell RJ, Cross AH, Laufer TM (2011) Limited sufficiency of antigen presentation by dendritic cells in models of central nervous system autoimmunity. J Autoimmun 36(1):56–64

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  65. Yogev N, Frommer F, Lukas D, Kautz-Neu K, Karram K, Ielo D, von Stebut E, Probst HC, van den Broek M, Riethmacher D, Birnberg T, Blank T, Reizis B, Korn T, Wiendl H, Jung S, Prinz M, Kurschus FC, Waisman A (2012) Dendritic cells ameliorate autoimmunity in the CNS by controlling the homeostasis of PD-1 receptor(+) regulatory T cells. Immunity 37(2):264–275

    Article  CAS  PubMed  Google Scholar 

  66. Almolda B, Gonzalez B, Castellano B (2011) Antigen presentation in EAE: role of microglia, macrophages and dendritic cells. Front Biosci 16:1157–1171

    Article  CAS  Google Scholar 

  67. Anandasabapathy N, Victora GD, Meredith M, Feder R, Dong B, Kluger C, Yao K, Dustin ML, Nussenzweig MC, Steinman RM, Liu K (2011) Flt3L controls the development of radiosensitive dendritic cells in the meninges and choroid plexus of the steady-state mouse brain. J Exp Med 208(8):1695–1705

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  68. Mack FL, Vanderlugt-Castaneda CL, Neville KL, Miller SD (2003) Microglia are activated to become competent antigen presenting and effector cells in the inflammatory environment of the Theiler’s virus model of multiple sclerosis. J Neuroimmunol 144:68–79

    Article  CAS  PubMed  Google Scholar 

  69. Juedes AE, Ruddle NH (2001) Resident and infiltrating central nervous system APCs regulate the emergence and resolution of experimental autoimmune encephalomyelitis. J Immunol 166(8):5168–5175

    Article  CAS  PubMed  Google Scholar 

  70. Olson JK, Girvin AM, Miller SD (2001) Direct activation of innate and antigen-presenting functions of microglia following infection with Theiler's virus. J Virol 75(20):9780–9789

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  71. Chastain EM, Duncan DS, Rodgers JM, Miller SD (2011) The role of antigen presenting cells in multiple sclerosis. Biochim Biophys Acta 1812(2):265–274

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  72. Dhodapkar MV, Steinman RM, Krasovsky J, Munz C, Bhardwaj N (2001) Antigen-specific inhibition of effector T cell function in humans after injection of immature dendritic cells. J Exp Med 193(2):233–238

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  73. Pender MP, McCombe PA, Yoong G, Nguyen KB (1992) Apoptosis of alpha beta T lymphocytes in the nervous system in experimental autoimmune encephalomyelitis: its possible implications for recovery and acquired tolerance. J Autoimmun 5(4):401–410

    Article  CAS  PubMed  Google Scholar 

  74. Schmied M, Breitschopf H, Gold R, Zischler H, Rothe G, Wekerle H, Lassmann H (1993) Apoptosis of T lymphocytes in experimental autoimmune encephalomyelitis. Evidence for programmed cell death as a mechanism to control inflammation in the brain. Am J Pathol 143(2):446–452

    PubMed Central  CAS  PubMed  Google Scholar 

  75. Hiremath MM, Saito Y, Knapp GW, Ting JP, Suzuki K, Matsushima GK (1998) Microglia/macrophage accumulation during cuprizone-induced demyelination in C57BL/6 mice. J Immunol 92(1–2):38–49

    CAS  Google Scholar 

  76. Pasquini LA, Calatayud CA, BertoneUna AL, Millet V, Pasquini JM, Soto EF (2007) The neurotoxic effect of cuprizone on oligodendrocytes depends on the presence of pro-inflammatory cytokines secreted by microglia. Neurochem Res 32(2):279–292

    Article  CAS  PubMed  Google Scholar 

  77. Remington LT, Babcock AA, Zehntner SP, Owens T (2007) Microglial recruitment, activation, and proliferation in response to primary demyelination. Am J Pathol 170(5):1713–1724

    Article  PubMed Central  PubMed  Google Scholar 

  78. Hassan GS, Mourad W (2011) An unexpected role for MHC class II. Nat Immunol 12(5):375–376

    Article  CAS  PubMed  Google Scholar 

  79. Bartholomäus I, Kawakami N, Odoardi F, Schläger C, Miljkovic D, Ellwart JW, Klinkert WE, Flügel-Koch C, Issekutz TB, Wekerle H, Flügel A (2009) Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions. Nature 462(7269):94–98

    Article  PubMed  CAS  Google Scholar 

  80. Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, Ransohoff RM, Greenberg ME, Barres BA, Stevens B (2012) Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74(4):691–705

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  81. Sierra A, Encinas JM, Deudero JJ, Chancey JH, Enikolopov G, Overstreet-Wadiche LS, Tsirka SE, Maletic-Savatic M (2010) Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell 7(4):483–495

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  82. Gitik M, Liraz-Zaltsman S, Oldenborg PA, Reichert F, Rotshenker S (2011) Myelin down-regulates myelin phagocytosis by microglia and macrophages through interactions between CD47 on myelin and SIRPα (signal regulatory protein-α) on phagocytes. J Neuroinflammation 8:24

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  83. Smith ME (2001) Phagocytic properties of microglia in vitro: implications for a role in multiple sclerosis and EAE. Microsc Res Tech 54(2):81–94

    Article  CAS  PubMed  Google Scholar 

  84. Takahashi K, Rochford CD, Neumann H (2005) Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J Exp Med 201(4):647–65

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  85. Colonna M, Facchetti F (2003) TREM-1 (triggering receptor expressed on myeloid cells): a new player in acute inflammatory responses. J Infect Dis 187(Suppl 2):S397–401

    Article  CAS  PubMed  Google Scholar 

  86. Bitsch A, Kuhlmann T, Da Costa C, Bunkowski S, Polak T, Brück W (2000) Tumor necrosis factor alpha mRNA expression in early multiple sclerosis lesions: correlation with demyelinating activity and oligodendrocyte pathology. Glia 29(4):366–375

    Article  CAS  PubMed  Google Scholar 

  87. Hofman FM, Hinton DR, Johnson K, Merrill JE (1989) Tumor necrosis factor identified in multiple sclerosis brain. J Exp Med 170(2):607–612

    Article  CAS  PubMed  Google Scholar 

  88. Schmitz T, Chew LJ (2008) Cytokines and myelination in the central nervous system. Sci World J 8:1119–1147

    Article  CAS  Google Scholar 

  89. Haji N, Mandolesi G, Gentile A, Sacchetti L, Fresegna D, Rossi S, Musella A, Sepman H, Motta C, Studer V, De Chiara V, Bernardi G, Strata P, Centonze D (2012) TNF-α-mediated anxiety in a mouse model of multiple sclerosis. Exp Neurol 237(2):296–303

    Article  CAS  PubMed  Google Scholar 

  90. Sakurai H, Nishi A, Sato N, Mizukami J, Miyoshi H, Sugita T (2002) TAK1-TAB1 fusion protein: a novel constitutively active mitogen-activated protein kinase kinasekinase that stimulates AP-1 and NFkB signaling pathways. Biochem Biophys Res Commun 297:1277–1281

    Article  CAS  PubMed  Google Scholar 

  91. Sutton C, Brereton C, Keogh B, Mills KH, Lavelle EC (2006) A crucial role for interleukin (IL)-1 in the induction of IL-17-producing T cells that mediate autoimmune encephalomyelitis. J Exp Med 203(7):1685–1691

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  92. Samoilova EB, Horton JL, Hilliard B, Liu TS, Chen Y (1998) IL-6-deficient mice are resistant to experimental autoimmune encephalomyelitis: roles of IL-6 in the activation and differentiation of autoreactive T cells. J Immunol 161(12):6480–6486

    CAS  PubMed  Google Scholar 

  93. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441(7090):235–238

    Article  CAS  PubMed  Google Scholar 

  94. Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, McClanahan T, Kastelein RA, Cua DJ (2005) IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 201(2):233–240

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  95. Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, Vega F, Yu N, Wang J, Singh K, Zonin F, Vaisberg E, Churakova T, Liu M, Gorman D, Wagner J, Zurawski S, Liu Y, Abrams JS, Moore KW, Rennick D, de Waal-Malefyt R, Hannum C, Bazan JF, Kastelein RA (2000) Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 13(5):715–725

    Article  CAS  PubMed  Google Scholar 

  96. Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B (2006) TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24(2):179–189

    Article  CAS  PubMed  Google Scholar 

  97. Leonard JP, Waldburger KE, Goldman SJ (1995) Prevention of experimental autoimmune encephalomyelitis by antibodies against interleukin 12. J Exp Med 181(1):381–386

    Article  CAS  PubMed  Google Scholar 

  98. Becher B, Durell BG, Noelle RJ (2002) Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12. J Clin Invest 110(4):493–497

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  99. Gran B, Zhang GX, Yu S, Li J, Chen XH, Ventura ES, Kamoun M, Rostami A (2002) IL-12p35-deficient mice are susceptible to experimental autoimmune encephalomyelitis: evidence for redundancy in the IL-12 system in the induction of central nervous system autoimmune demyelination. J Immunol 169(12):7104–7110

    Article  CAS  PubMed  Google Scholar 

  100. Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B, Lucian L, To W, Kwan S, Churakova T, Zurawski S, Wiekowski M, Lira SA, Gorman D, Kastelein RA, Sedgwick JD (2003) Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421(6924):744–748

    Article  CAS  PubMed  Google Scholar 

  101. Gyülvészi G, Haak S, Becher B (2009) IL-23-driven encephalo-tropism and Th17 polarization during CNS-inflammation in vivo. Eur J Immunol 39(7):1864–1869

    Article  PubMed  CAS  Google Scholar 

  102. Croxford A, Mair F, Becher B (2012) IL-23: one cytokine in control of autoimmunity. Eur J Immunol 42:2263–2273

    Article  CAS  PubMed  Google Scholar 

  103. Codarri L, Gyulveszi G, Tosevski V, Hesske L, Fontana A, Magnenat L, Suter T, Becher B (2011) RORγtdrived production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat Immunol 12(6):560–567

    Article  CAS  PubMed  Google Scholar 

  104. El-Behi M, Ciric B, Dai H, Yan Y, Cullimore M, Safavi F, Zhang GX, Dittel B, Rostami A (2011) The encephalitogenicity of Th17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF. Nat Immunol 12(6):568–585

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  105. Kurschus FC, Croxford AL, Heinen AP, Wortge S, Ielo D, Waisman A (2010) Genetic proof for the transient nature of the Th17 phenotype. Eur J Immunol 40(12):3336–3346

    Article  CAS  PubMed  Google Scholar 

  106. Hirota K, Duarte JH, Veldhoen M, Hornsby E, Li Y, Cua DJ, Ahlfors H, Wilhelm C, Tolaini M, Menzel U, Garefalaki A, Potocnik AJ, Stockinger B (2011) Fate mapping of IL-17-producing T cells in inflammatory responses. Nat Immunol 12(3):255–263

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  107. Li J, Gran B, Zhang GX, Ventura ES, Siglienti I, Rostami A, Kamoun M (2003) Differential expression and regulation of IL-23 and IL-12 subunits and receptors in adult mouse microglia. J Neurol Sci 215(1–2):95–103

    Article  CAS  PubMed  Google Scholar 

  108. Becher B, Durell BG, Noelle RJ (2003) IL-23 produced by CNS-resident cells controls T cell encephalitogenicity during the effector phase of experimental autoimmune encephalomyelitis. J Clin Invest 112(8):1186–1191

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  109. Thakker P, Leach MW, Kuang W, Benoit SE, Leonard JP, Marusic S (2007) IL-23 is critical in the induction but not in the effector phase of experimental autoimmune encephalomyelitis. J Immunol 178(4):2589–2598

    Article  CAS  PubMed  Google Scholar 

  110. Falcone M, Rajan AJ, Bloom BR, Brosnan CF (1998) A critical role for IL-4 in regulating disease severity in experimental allergic encephalomyelitis as demonstrated in IL-4-deficient C57BL/6 mice and BALB/c mice. J Immunol 160(10):4822–4830

    CAS  PubMed  Google Scholar 

  111. Ponomarev ED, Maresz K, Tan Y, Dittel BN (2007) CNS-derived interleukin-4 is essential for the regulation of autoimmune inflammation and induces a state of alternative activation in microglial cells. J Neurosci 27(40):10714–10721

    Article  CAS  PubMed  Google Scholar 

  112. Butovsky O, Landa G, Kunis G, Ziv Y, Avidan H, Greenberg N, Schwartz A, Smirnov I, Pollack A, Jung S, Schwartz M (2006) Induction and blockage of oligodendrogenesis by differently activated microglia in an animal model of multiple sclerosis. J Clin Invest 116(4):905–915

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  113. Bettelli E, Das MP, Howard ED, Weiner HL, Sobel RA, Kuchroo VK (1998) IL-10 is critical in the regulation of autoimmune encephalomyelitis as demonstrated by studies of IL-10- and IL-4-deficient and transgenic mice. J Immunol 161(7):3299–3306

    CAS  PubMed  Google Scholar 

  114. Zhang X, Koldzic DN, Izikson L, Reddy J, Nazareno RF, Sakaguchi S, Kuchroo VK, Weiner HL (2004) IL-10 is involved in the suppression of experimental autoimmune encephalomyelitis by CD25+CD4+ regulatory T cells. Int Immunol 16(2):249–256

    Article  CAS  PubMed  Google Scholar 

  115. Semple BD, Kossmann T, Morganti-Kossmann MC (2010) Role of chemokines in CNS health and pathology: a focus on the CCL2/CCR2 and CXCL8/CXCR2 networks. J Cereb Blood Flow Metab 30(3):459–473

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  116. Stamatovic SM, Shakui P, Keep RF, Moore BB, Kunkel SL, Van Rooijen N, Andjelkovic AV (2005) Monocyte chemoattractant protein-1 regulation of blood–brain barrier permeability. J Cereb Blood Flow Metab 25(5):593–606

    Article  CAS  PubMed  Google Scholar 

  117. Mildner A, Mack M, Schmidt H, Brück W, Djukic M, Zabel MD, Hille A, Priller J, Prinz M (2009) CCR2+Ly-6Chi monocytes are crucial for the effector phase of autoimmunity in the central nervous system. Brain 132(9):2487–2500

    Article  PubMed  Google Scholar 

  118. Brühl H, Cihak J, Plachý J, Kunz-Schughart L, Niedermeier M, Denzel A, Rodriguez Gomez M, Talke Y, Luckow B, Stangassinger M, Mack M (2007) Targeting of Gr-1+, CCR2+ monocytes in collagen-induced arthritis. Arthritis Rheum 56(9):2975–2985

    Article  PubMed  CAS  Google Scholar 

  119. Huang DR, Wang J, Kivisakk P, Rollins BJ, Ransohoff RM (2001) Absence of monocyte chemoattractant protein 1 in mice leads to decreased local macrophage recruitment and antigen-specific T helper cell type 1 immune response in experimental autoimmune encephalomyelitis. J Exp Med 193(6):713–726

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  120. Paul D, Ge S, Lemire Y, Jellison ER, Serwanski DR, Ruddle NH, Pachter JS (2014) Cell-selective knockout and 3D confocal image analysis reveals separate roles for astrocyte-and endothelial-derived CCL2 in neuroinflammation. J Neuroinflammation 11:10

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  121. Moreno M, Bannerman P, Ma J, Guo F, Miers L, Soulika AM, Pleasure D (2014) Conditional ablation of astroglial CCL2 suppresses CNS accumulation of M1 macrophages and preserves axons with MOG peptide EAE. J Neurosci 34(24):8175–8185

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  122. Ge S, Murugesan N, Pachter JS (2009) Astrocyte- and endothelial-targeted CCL2 conditional knockout mice: critical tools for studying the pathogenesis of neuroinflammation. J Mol Neurosci 39(1–2):269–283

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  123. Sato W, Aranami T, Yamamura T (2007) Cutting edge: human Th17 cells are identified as bearing CCR2+CCR5- phenotype. J Immunol 178:7525–7529

    Article  CAS  PubMed  Google Scholar 

  124. Webb A, Johnson A, Fortunato M, Platt A, Crabbe T, Christie MI, Watt GF, Ward SG, Jopling LA (2008) Evidence for PI-3K-dependent migration of Th17-polarized cells in response to CCR2 and CCR6 agonists. J Leukoc Biol 84:1202–1212

    Article  CAS  PubMed  Google Scholar 

  125. Reboldi A, Coisne C, Baumjohann D, Benvenuto F, Bottinelli D, Lira S, Uccelli A, Lanzavecchia A, Engelhardt B, Sallusto F (2009) C-C chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE. Nat Immunol 10(5):514–523

    Article  CAS  PubMed  Google Scholar 

  126. Dogan RN, Long N, Forde E, Dennis K, Kohm AP, Miller SD, Karpus WJ (2011) CCL22 regulates experimental autoimmune encephalomyelitis by controlling inflammatory macrophage accumulation and effector function. J Leukoc Biol 89(1):93–104

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  127. Forde EA, Dogan RN, Karpus WJ (2011) CCR4 contributes to the pathogenesis of experimental autoimmune encephalomyelitis by regulating inflammatory macrophage function. J Neuroimmunol 236(1–2):17–26

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  128. Getts DR, Terry RL, Getts MT, Deffrasnes C, Muller M, van Verden C, Ashhurst TM, Chami B, McCarthy D, Wu H, Ma J, Martin A, Shae LD, Witting P, Kansas GS, Kuhn J, Hafezi W, Campbell IL, Reilly D, Say J, Brown L, White MY, Cordwell SJ, Chadben SJ, Thorp EB, Bao S, Miller SD, King NJ (2014) Therapeutic inflammatory monocyte modulation using immune-modifying microparticles. Sci Transl Med 6(219):219ra7

    Article  PubMed Central  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by a grant of the Israel Science Foundation to SJ. We thank the members of the Jung laboratory, in particular, Yochai Wolf and Neta Barashi for critical reading of the manuscript and helpful comments.

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  1. Department of Immunology, Weizmann Institute of Science, Rehovot, 76100, Israel

    Anat Shemer & Steffen Jung

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  1. Anat Shemer
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  2. Steffen Jung
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Correspondence to Steffen Jung.

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This article is a contribution to the Special Issue on: Role of Astrocytes and Microglia in CNS Inflammation - Guest Editor: Francisco Quintana

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Shemer, A., Jung, S. Differential roles of resident microglia and infiltrating monocytes in murine CNS autoimmunity. Semin Immunopathol 37, 613–623 (2015). https://doi.org/10.1007/s00281-015-0519-z

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