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
Holmoy T, Hestvik AL (2008) Multiple sclerosis: immunopathogenesis and controversies in defining the cause. Curr Opin Infect Dis 21(3):271–278
Lisak RP (2007) Neurodegenaretion in multiple sclerosis: defining the problem. Neurology 68(22):43–54
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
Croxford AL, Kurschus FC, Waisman A (2011) Mouse models for multiple sclerosis: historical facts and future implication. Biochim Biophys Acta 1812(2):177–183
Hemmer B, Archelos JJ, Hartung HP (2002) New concepts in the immunopathogenesis of multiple sclerosis. Nat Rev Neurosci 3(4):291–301
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
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
Ranshoff R, Perry V (2009) Microglial physiology: unique stimuli, specialized responses. Annu Rev Immunol 27:119–145
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
Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314–1318
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
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
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
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
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
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
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
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
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
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
Mildner A, Yona S, Jung S (2013) A close encounter of the third kind: monocyte-derived cells. Adv Immunol 120:69–103
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
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
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
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
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
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
Geissmann F, Jung S, Littman DR (2003) Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19(1):71–82
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
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
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
Serbina NV, Shi C, Pamer EG (2012) Monocyte-mediated immune defense against murine Listeria monocytogenes infection. Adv Immunol 113:119–134
Segura E, Amigorena S (2013) Inflammatory dendritic cells in mice and humans. Trends Immunol 34(9):440–445
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
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
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
Noy R, Pollard JW (2014) Tumor-associated macrophages: from mechanisms to therapy. Immunity 41(1):49–61
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
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
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
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
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
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
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
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
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
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
Mills CD (2012) M1 and M2 macrophages: oracles of health and disease. Crit Rev Immunol 32(6):463–488
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
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
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
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
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
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
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
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
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
Jiang Z, Jiang JX, Zhang GX (2014) Macrophages: a double-edged sword in experimental autoimmune encephalomyelitis. Immunol Lett 160(1):17–22
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
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
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
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
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
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
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
Almolda B, Gonzalez B, Castellano B (2011) Antigen presentation in EAE: role of microglia, macrophages and dendritic cells. Front Biosci 16:1157–1171
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
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
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
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
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
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
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
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
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
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
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
Hassan GS, Mourad W (2011) An unexpected role for MHC class II. Nat Immunol 12(5):375–376
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
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
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
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
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
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
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
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
Hofman FM, Hinton DR, Johnson K, Merrill JE (1989) Tumor necrosis factor identified in multiple sclerosis brain. J Exp Med 170(2):607–612
Schmitz T, Chew LJ (2008) Cytokines and myelination in the central nervous system. Sci World J 8:1119–1147
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
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
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
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
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
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
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
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
Leonard JP, Waldburger KE, Goldman SJ (1995) Prevention of experimental autoimmune encephalomyelitis by antibodies against interleukin 12. J Exp Med 181(1):381–386
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
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
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
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
Croxford A, Mair F, Becher B (2012) IL-23: one cytokine in control of autoimmunity. Eur J Immunol 42:2263–2273
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Sato W, Aranami T, Yamamura T (2007) Cutting edge: human Th17 cells are identified as bearing CCR2+CCR5- phenotype. J Immunol 178:7525–7529
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
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
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
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
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
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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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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DOI: https://doi.org/10.1007/s00281-015-0519-z