Skip to main content

Advertisement

Log in

Do not judge a cell by its cover—diversity of CNS resident, adjoining and infiltrating myeloid cells in inflammation

  • Review
  • Published:
Seminars in Immunopathology Aims and scope Submit manuscript

Abstract

Specialized populations of tissue-resident myeloid cells inhabit every organ of the body. While many of these populations appear similar morphologically and phenotypically, they exhibit great functional diversity. The central nervous system (CNS), as an immune privileged organ, possesses a unique tissue-resident macrophage population, the microglia, as well as numerous myeloid cell subsets at its boarders and barriers in CNS-adjoining tissues, namely the meninges, the perivascular space, and the choroid plexus. Recent research has added much to our knowledge about microglia, whereas the populations of CNS-surrounding phagocytes are just starting to be appreciated. As guardians of CNS homeostasis, these myeloid cells perform immune surveillance and immune modulatory tasks in health and disease. As such, microglia and CNS-surrounding antigen-presenting cells have been shown to be crucially involved not only in the initiation and progression but also resolution of multiple sclerosis (MS). MS and its rodent model, experimental autoimmune encephalomyelitis, are autoimmune inflammatory demyelinating CNS pathologies. While some crucial aspects of the disease pathogenesis have been solved, much of the complex involvement and interplay of the innate immune compartment remains yet to be clarified. Here, we will discuss the current understanding of the scope of phenotypes and functions of myeloid cells involved in CNS neuroinflammation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Epelman S, Lavine KJ, Randolph GJ (2014) Origin and functions of tissue macrophages. Immunity 41:21–35

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Randolph GJ (2014) A macrophage revolution-and beyond. Immunol Rev 262:5–8

    Article  PubMed  Google Scholar 

  3. 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 (2012) Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat Immunol 13:1118–28

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Ginhoux F, Jung S (2014) Monocytes and macrophages: developmental pathways and tissue homeostasis. Nat Rev Immunol 14:392–404

    Article  CAS  PubMed  Google Scholar 

  5. 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 211:2151–8

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Hashimoto D, Chow A, Noizat C, Teo P, Beasley MB, Leboeuf M, Becker CD, See P, Price J, Lucas D, Greter M, Mortha A, Boyer SW, Forsberg EC, Tanaka M, van Rooijen N, Garcia-Sastre A, Stanley ER, Ginhoux F, Frenette PS, Merad M (2013) Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 38:792–804

    Article  CAS  PubMed  Google Scholar 

  7. Epelman S, Lavine KJ, Beaudin AE, Sojka DK, Carrero JA, Calderon B, Brija T, Gautier EL, Ivanov S, Satpathy AT, Schilling JD, Schwendener R, Sergin I, Razani B, Forsberg EC, Yokoyama WM, Unanue ER, Colonna M, Randolph GJ, Mann DL (2014) Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation. Immunity 40:91–104

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. 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 15:929–37

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Kierdorf K, Erny D, Goldmann T, Sander V, Schulz C, Perdiguero EG, Wieghofer P, Heinrich A, Riemke P, Holscher C, Muller 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 16:273–80

    Article  CAS  PubMed  Google Scholar 

  10. Prinz M, Priller J (2014) Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nat Rev Neurosci 15:300–12

    Article  CAS  PubMed  Google Scholar 

  11. Dyrna F, Hanske S, Krueger M, Bechmann I (2013) The blood–brain barrier. J Neuroimmune Pharmacol 8:763–73

    Article  PubMed  Google Scholar 

  12. Ousman SS, Kubes P (2012) Immune surveillance in the central nervous system. Nat Neurosci 15:1096–101

    Article  CAS  PubMed  Google Scholar 

  13. Goldmann T, Prinz M (2013) Role of microglia in CNS autoimmunity. Clin Dev Immunol 2013:208093

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  14. Prinz M, Tay TL, Wolf Y, Jung S (2014) Microglia: unique and common features with other tissue macrophages. Acta Neuropathol 128:319–31

    Article  PubMed  Google Scholar 

  15. Saijo K, Glass CK (2011) Microglial cell origin and phenotypes in health and disease. Nat Rev Immunol 11:775–87

    Article  CAS  PubMed  Google Scholar 

  16. McMenamin PG (1999) Distribution and phenotype of dendritic cells and resident tissue macrophages in the dura mater, leptomeninges, and choroid plexus of the rat brain as demonstrated in wholemount preparations. J Comp Neurol 405:553–62

    Article  CAS  PubMed  Google Scholar 

  17. McMenamin PG, Wealthall RJ, Deverall M, Cooper SJ, Griffin B (2003) Macrophages and dendritic cells in the rat meninges and choroid plexus: three-dimensional localisation by environmental scanning electron microscopy and confocal microscopy. Cell Tissue Res 313:259–69

    Article  PubMed  Google Scholar 

  18. Chinnery HR, Ruitenberg MJ, McMenamin PG (2010) Novel characterization of monocyte-derived cell populations in the meninges and choroid plexus and their rates of replenishment in bone marrow chimeric mice. J Neuropathol Exp Neurol 69:896–909

    Article  PubMed  Google Scholar 

  19. Bogie JF, Stinissen P, Hendriks JJ (2014) Macrophage subsets and microglia in multiple sclerosis. Acta Neuropathol 128:191–213

    Article  CAS  PubMed  Google Scholar 

  20. Kivisakk P, Imitola J, Rasmussen S, Elyaman W, Zhu B, Ransohoff RM, Khoury SJ (2009) Localizing central nervous system immune surveillance: meningeal antigen-presenting cells activate T cells during experimental autoimmune encephalomyelitis. Ann Neurol 65:457–69

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. 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 208:1695–705

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. 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 11:328–34

    Article  CAS  PubMed  Google Scholar 

  23. Hafler DA (2004) Multiple sclerosis. J Clin Invest 113:788–94

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Lucchinetti C, Bruck W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H (2000) Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 47:707–17

    Article  CAS  PubMed  Google Scholar 

  25. Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG (2000) Multiple sclerosis. N Engl J Med 343:938–52

    Article  CAS  PubMed  Google Scholar 

  26. Hafler DA, Compston A, Sawcer S, Lander ES, Daly MJ, De Jager PL, de Bakker PI, Gabriel SB, Mirel DB, Ivinson AJ, Pericak-Vance MA, Gregory SG, Rioux JD, McCauley JL, Haines JL, Barcellos LF, Cree B, Oksenberg JR, Hauser SL (2007) Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med 357:851–62

    Article  CAS  PubMed  Google Scholar 

  27. Sawcer S, Hellenthal G, Pirinen M, Spencer CC, Patsopoulos NA et al (2011) Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476:214–9

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Yadav SK, Mindur JE, Ito K, Dhib-Jalbut S (2015) Advances in the immunopathogenesis of multiple sclerosis. Curr Opin Neurol 28(3):206–19

    Article  CAS  PubMed  Google Scholar 

  29. Lucchinetti CF, Popescu BF, Bunyan RF, Moll NM, Roemer SF, Lassmann H, Bruck W, Parisi JE, Scheithauer BW, Giannini C, Weigand SD, Mandrekar J, Ransohoff RM (2011) Inflammatory cortical demyelination in early multiple sclerosis. N Engl J Med 365:2188–97

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Simmons SB, Pierson ER, Lee SY, Goverman JM (2013) Modeling the heterogeneity of multiple sclerosis in animals. Trends Immunol 34:410–22

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Stromnes IM, Goverman JM (2006) Passive induction of experimental allergic encephalomyelitis. Nat Protoc 1:1952–60

    Article  CAS  PubMed  Google Scholar 

  32. Stromnes IM, Goverman JM (2006) Active induction of experimental allergic encephalomyelitis. Nat Protoc 1:1810–9

    Article  CAS  PubMed  Google Scholar 

  33. Shechter R, London A, Schwartz M (2013) Orchestrated leukocyte recruitment to immune-privileged sites: absolute barriers versus educational gates. Nat Rev Immunol 13:206–18

    Article  CAS  PubMed  Google Scholar 

  34. Huitinga I, van Rooijen N, de Groot CJ, Uitdehaag BM, Dijkstra CD (1990) Suppression of experimental allergic encephalomyelitis in Lewis rats after elimination of macrophages. J Exp Med 172:1025–33

    Article  CAS  PubMed  Google Scholar 

  35. Tran EH, Hoekstra K, van Rooijen N, Dijkstra CD, Owens T (1998) Immune invasion of the central nervous system parenchyma and experimental allergic encephalomyelitis, but not leukocyte extravasation from blood, are prevented in macrophage-depleted mice. J Immunol 161:3767–75

    CAS  PubMed  Google Scholar 

  36. 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 130:2800–15

    Article  PubMed Central  PubMed  Google Scholar 

  37. Mildner A, Mack M, Schmidt H, Bruck 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 132:2487–500

    Article  PubMed  Google Scholar 

  38. 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 211:1533–49

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Miron VE, Boyd A, Zhao JW, Yuen TJ, Ruckh JM, Shadrach JL, van Wijngaarden P, Wagers AJ, Williams A, Franklin RJ, ffrench-Constant C (2013) M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat Neurosci 16:1211–8

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Pinto AR, Godwin JW, Rosenthal NA (2014) Macrophages in cardiac homeostasis, injury responses and progenitor cell mobilisation. Stem Cell Res 13:705–14

    Article  CAS  PubMed  Google Scholar 

  41. Gertig U, Hanisch UK (2014) Microglial diversity by responses and responders. Front Cell Neurosci 8:101

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  42. Butovsky O, Jedrychowski MP, Moore CS, Cialic R, Lanser AJ, Gabriely G, Koeglsperger T, Dake B, Wu PM, Doykan CE, Fanek Z, Liu L, Chen Z, Rothstein JD, Ransohoff RM, Gygi SP, Antel JP, Weiner HL (2014) Identification of a unique TGF-beta-dependent molecular and functional signature in microglia. Nat Neurosci 17:131–43

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Geissmann F, Manz MG, Jung S, Sieweke MH, Merad M, Ley K (2010) Development of monocytes, macrophages, and dendritic cells. Science 327:656–61

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Schulz C, Gomez Perdiguero E, Chorro L, Szabo-Rogers H, Cagnard N, Kierdorf K, Prinz M, Wu B, Jacobsen SE, Pollard JW, Frampton J, Liu KJ, Geissmann F (2012) A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336:86–90

    Article  CAS  PubMed  Google Scholar 

  45. 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 14:1142–9

    Article  CAS  PubMed  Google Scholar 

  46. Vainchtein ID, Vinet J, Brouwer N, Brendecke S, Biagini G, Biber K, Boddeke HW, Eggen BJ (2014) In acute experimental autoimmune encephalomyelitis, infiltrating macrophages are immune activated, whereas microglia remain immune suppressed. Glia 62:1724–35

    Article  CAS  PubMed  Google Scholar 

  47. Ford AL, Goodsall AL, Hickey WF, Sedgwick JD (1995) Normal adult ramified microglia separated from other central nervous system macrophages by flow cytometric sorting. Phenotypic differences defined and direct ex vivo antigen presentation to myelin basic protein-reactive CD4+ T cells compared. J Immunol 154:4309–21

    CAS  PubMed  Google Scholar 

  48. Hickman SE, Kingery ND, Ohsumi TK, Borowsky ML, Wang LC, Means TK, El Khoury J (2013) The microglial sensome revealed by direct RNA sequencing. Nat Neurosci 16:1896–905

    Article  CAS  PubMed  Google Scholar 

  49. Goldmann T, Zeller N, Raasch J, Kierdorf K, Frenzel K, Ketscher L, Basters A, Staszewski O, Brendecke SM, Spiess A, Tay TL, Kreutz C, Timmer J, Mancini GM, Blank T, Fritz G, Biber K, Lang R, Malo D, Merkler D, Heikenwalder M, Knobeloch KP, Prinz M (2015) USP18 lack in microglia causes destructive interferonopathy of the mouse brain. EMBO J 34(12):1612–29

    Article  CAS  PubMed  Google Scholar 

  50. Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314–8

    Article  CAS  PubMed  Google Scholar 

  51. Paolicelli RC, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P, Giustetto M, Ferreira TA, Guiducci E, Dumas L, Ragozzino D, Gross CT (2011) Synaptic pruning by microglia is necessary for normal brain development. Science 333:1456–8

    Article  CAS  PubMed  Google Scholar 

  52. Tremblay ME, Lowery RL, Majewska AK (2010) Microglial interactions with synapses are modulated by visual experience. PLoS Biol 8, e1000527

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  53. Zhan Y, Paolicelli RC, Sforazzini F, Weinhard L, Bolasco G, Pagani F, Vyssotski AL, Bifone A, Gozzi A, Ragozzino D, Gross CT (2014) Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior. Nat Neurosci 17:400–6

    Article  CAS  PubMed  Google Scholar 

  54. Marin-Teva JL, Dusart I, Colin C, Gervais A, van Rooijen N, Mallat M (2004) Microglia promote the death of developing Purkinje cells. Neuron 41:535–47

    Article  CAS  PubMed  Google Scholar 

  55. Benveniste EN (1997) Role of macrophages/microglia in multiple sclerosis and experimental allergic encephalomyelitis. J Mol Med (Berl) 75:165–73

    Article  CAS  Google Scholar 

  56. Brown DA, Sawchenko PE (2007) Time course and distribution of inflammatory and neurodegenerative events suggest structural bases for the pathogenesis of experimental autoimmune encephalomyelitis. J Comp Neurol 502:236–60

    Article  PubMed  Google Scholar 

  57. Herder V, Iskandar CD, Kegler K, Hansmann F, Elmarabet SA, Khan MA, Kalkuhl A, Deschl U, Baumgartner W, Ulrich R, Beineke A (2014) Dynamic changes of microglia/macrophage M1 and M2 polarization in Theiler’s murine encephalomyelitis. Brain Pathol. doi: 10.1111/bpa.12238

  58. Heppner FL, Greter M, Marino D, Falsig J, Raivich G, Hovelmeyer N, Waisman A, Rulicke T, Prinz M, Priller J, Becher B, Aguzzi A (2005) Experimental autoimmune encephalomyelitis repressed by microglial paralysis. Nat Med 11:146–52

    Article  CAS  PubMed  Google Scholar 

  59. Ding Z, Mathur V, Ho PP, James ML, Lucin KM, Hoehne A, Alabsi H, Gambhir SS, Steinman L, Luo J, Wyss-Coray T (2014) Antiviral drug ganciclovir is a potent inhibitor of microglial proliferation and neuroinflammation. J Exp Med 211:189–98

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  60. 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 

  61. Popovic N, Schubart A, Goetz BD, Zhang SC, Linington C, Duncan ID (2002) Inhibition of autoimmune encephalomyelitis by a tetracycline. Ann Neurol 51:215–23

    Article  CAS  PubMed  Google Scholar 

  62. Lewis ND, Hill JD, Juchem KW, Stefanopoulos DE, Modis LK (2014) RNA sequencing of microglia and monocyte-derived macrophages from mice with experimental autoimmune encephalomyelitis illustrates a changing phenotype with disease course. J Neuroimmunol 277:26–38

    Article  CAS  PubMed  Google Scholar 

  63. Zhan XX, Liu Y, Yang JF, Wang GY, Mu L, Zhang TS, Xie XL, Wang JH, Liu YM, Kong QF, Li HL, Sun B (2013) All-trans-retinoic acid ameliorates experimental allergic encephalomyelitis by affecting dendritic cell and monocyte development. Immunology 138:333–45

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  64. Hanisch UK (2002) Microglia as a source and target of cytokines. Glia 40:140–55

    Article  PubMed  Google Scholar 

  65. Merson TD, Binder MD, Kilpatrick TJ (2010) Role of cytokines as mediators and regulators of microglial activity in inflammatory demyelination of the CNS. Neuromolecular Med 12:99–132

    Article  CAS  PubMed  Google Scholar 

  66. 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 201:233–40

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  67. Bettelli E, Korn T, Oukka M, Kuchroo VK (2008) Induction and effector functions of T(H)17 cells. Nature 453:1051–7

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  69. Boven LA, Van Meurs M, Van Zwam M, Wierenga-Wolf A, Hintzen RQ, Boot RG, Aerts JM, Amor S, Nieuwenhuis EE, Laman JD (2006) Myelin-laden macrophages are anti-inflammatory, consistent with foam cells in multiple sclerosis. Brain 129:517–26

    Article  PubMed  Google Scholar 

  70. 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 27:10714–21

    Article  CAS  PubMed  Google Scholar 

  71. Prinz M, Priller J (2010) Tickets to the brain: role of CCR2 and CX3CR1 in myeloid cell entry in the CNS. J Neuroimmunol 224:80–4

    Article  CAS  PubMed  Google Scholar 

  72. Izikson L, Klein RS, Charo IF, Weiner HL, Luster AD (2000) Resistance to experimental autoimmune encephalomyelitis in mice lacking the CC chemokine receptor (CCR)2. J Exp Med 192:1075–80

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  73. 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 in mice with MOG peptide EAE. J Neurosci 34:8175–85

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  74. (1998) Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Lancet, 352:1498–504

  75. Teige I, Treschow A, Teige A, Mattsson R, Navikas V, Leanderson T, Holmdahl R, Issazadeh-Navikas S (2003) IFN-beta gene deletion leads to augmented and chronic demyelinating experimental autoimmune encephalomyelitis. J Immunol 170:4776–84

    Article  CAS  PubMed  Google Scholar 

  76. Prinz M, Schmidt H, Mildner A, Knobeloch KP, Hanisch UK, Raasch J, Merkler D, Detje C, Gutcher I, Mages J, Lang R, Martin R, Gold R, Becher B, Bruck W, Kalinke U (2008) Distinct and nonredundant in vivo functions of IFNAR on myeloid cells limit autoimmunity in the central nervous system. Immunity 28:675–86

    Article  CAS  PubMed  Google Scholar 

  77. Kocur M, Schneider R, Pulm AK, Bauer J, Kropp S, Gliem M, Ingwersen J, Goebels N, Alferink J, Prozorovski T, Aktas O, Scheu S (2015) IFNbeta secreted by microglia mediates clearance of myelin debris in CNS autoimmunity. Acta Neuropathol Commun 3:20

    Article  PubMed Central  PubMed  Google Scholar 

  78. Khorooshi R, Morch MT, Holm TH, Berg CT, Dieu RT, Draeby D, Issazadeh-Navikas S, Weiss S, Lienenklaus S, Owens T (2015) Induction of endogenous type I interferon within the central nervous system plays a protective role in experimental autoimmune encephalomyelitis. Acta Neuropathol 130(1):107–18

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  79. Kotter MR, Li WW, Zhao C, Franklin RJ (2006) Myelin impairs CNS remyelination by inhibiting oligodendrocyte precursor cell differentiation. J Neurosci 26:328–32

    Article  CAS  PubMed  Google Scholar 

  80. Neumann H, Kotter MR, Franklin RJ (2009) Debris clearance by microglia: an essential link between degeneration and regeneration. Brain 132:288–95

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  81. Nikic I, Merkler D, Sorbara C, Brinkoetter M, Kreutzfeldt M, Bareyre FM, Bruck W, Bishop D, Misgeld T, Kerschensteiner M (2011) A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis. Nat Med 17:495–9

    Article  CAS  PubMed  Google Scholar 

  82. Cash E, Zhang Y, Rott O (1993) Microglia present myelin antigens to T cells after phagocytosis of oligodendrocytes. Cell Immunol 147:129–38

    Article  CAS  PubMed  Google Scholar 

  83. 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 1103:179–91

    Article  CAS  PubMed  Google Scholar 

  84. Sosa RA, Murphey C, Ji N, Cardona AE, Forsthuber TG (2013) The kinetics of myelin antigen uptake by myeloid cells in the central nervous system during experimental autoimmune encephalomyelitis. J Immunol 191:5848–57

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  85. McMahon EJ, Bailey SL, Castenada CV, Waldner H, Miller SD (2005) Epitope spreading initiates in the CNS in two mouse models of multiple sclerosis. Nat Med 11:335–9

    Article  CAS  PubMed  Google Scholar 

  86. Tompkins SM, Padilla J, Dal Canto MC, Ting JP, Van Kaer L, Miller SD (2002) De novo central nervous system processing of myelin antigen is required for the initiation of experimental autoimmune encephalomyelitis. J Immunol 168:4173–83

    Article  CAS  PubMed  Google Scholar 

  87. Chastain EM, Duncan DS, Rodgers JM, Miller SD (2011) The role of antigen presenting cells in multiple sclerosis. Biochim Biophys Acta 1812:265–74

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  88. Wlodarczyk A, Lobner M, Cedile O, Owens T (2014) Comparison of microglia and infiltrating CD11c(+) cells as antigen presenting cells for T cell proliferation and cytokine response. J Neuroinflammation 11:57

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  89. Aloisi F, Ria F, Penna G, Adorini L (1998) Microglia are more efficient than astrocytes in antigen processing and in Th1 but not Th2 cell activation. J Immunol 160:4671–80

    CAS  PubMed  Google Scholar 

  90. Mildner A, Schmidt H, Nitsche M, Merkler D, Hanisch UK, Mack M, Heikenwalder M, Bruck W, Priller J, Prinz M (2007) Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions. Nat Neurosci 10:1544–53

    Article  CAS  PubMed  Google Scholar 

  91. Kierdorf K, Katzmarski N, Haas CA, Prinz M (2013) Bone marrow cell recruitment to the brain in the absence of irradiation or parabiosis bias. PLoS One 8, e58544

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  92. Goldmann T, Wieghofer P, Muller PF, Wolf Y, Varol D, Yona S, Brendecke SM, Kierdorf K, Staszewski O, Datta M, Luedde T, Heikenwalder M, Jung S, Prinz M (2013) A new type of microglia gene targeting shows TAK1 to be pivotal in CNS autoimmune inflammation. Nat Neurosci 16:1618–26

    Article  CAS  PubMed  Google Scholar 

  93. Wieghofer P, Knobeloch KP, Prinz M (2015) Genetic targeting of microglia. Glia 63:1–22

    Article  PubMed  Google Scholar 

  94. Derecki NC, Cronk JC, Lu Z, Xu E, Abbott SB, Guyenet PG, Kipnis J (2012) Wild-type microglia arrest pathology in a mouse model of Rett syndrome. Nature 484:105–9

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  95. de Graaf MT, Smitt PA, Luitwieler RL, van Velzen C, van den Broek PD, Kraan J, Gratama JW (2011) Central memory CD4+ T cells dominate the normal cerebrospinal fluid. Cytometry B Clin Cytom 80:43–50

    Article  PubMed  Google Scholar 

  96. Prinz M, Priller J, Sisodia SS, Ransohoff RM (2011) Heterogeneity of CNS myeloid cells and their roles in neurodegeneration. Nat Neurosci 14:1227–35

    Article  CAS  PubMed  Google Scholar 

  97. Prodinger C, Bunse J, Kruger M, Schiefenhovel F, Brandt C, Laman JD, Greter M, Immig K, Heppner F, Becher B, Bechmann I (2011) CD11c-expressing cells reside in the juxtavascular parenchyma and extend processes into the glia limitans of the mouse nervous system. Acta Neuropathol 121:445–58

    Article  CAS  PubMed  Google Scholar 

  98. Prineas JW, Wright RG (1978) Macrophages, lymphocytes, and plasma cells in the perivascular compartment in chronic multiple sclerosis. Lab Invest 38:409–21

    CAS  PubMed  Google Scholar 

  99. Holder GE, McGary CM, Johnson EM, Zheng R, John VT, Sugimoto C, Kuroda MJ, Kim WK (2014) Expression of the mannose receptor CD206 in HIV and SIV encephalitis: a phenotypic switch of brain perivascular macrophages with virus infection. J Neuroimmune Pharmacol 9:716–26

    Article  PubMed  PubMed Central  Google Scholar 

  100. Decimo I, Fumagalli G, Berton V, Krampera M, Bifari F (2012) Meninges: from protective membrane to stem cell niche. Am J Stem Cells 1:92–105

    PubMed Central  CAS  PubMed  Google Scholar 

  101. Zeisel A, Munoz-Manchado AB, Codeluppi S, Lonnerberg P, La Manno G, Jureus A, Marques S, Munguba H, He L, Betsholtz C, Rolny C, Castelo-Branco G, Hjerling-Leffler J, Linnarsson S (2015) Brain structure. Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq. Science 347:1138–42

    Article  CAS  PubMed  Google Scholar 

  102. Walker-Caulfield ME, Hatfield JK, Brown MA (2015) Dynamic changes in meningeal inflammation correspond to clinical exacerbations in a murine model of relapsing-remitting multiple sclerosis. J Neuroimmunol 278:112–22

    Article  CAS  PubMed  Google Scholar 

  103. Christy AL, Walker ME, Hessner MJ, Brown MA (2013) Mast cell activation and neutrophil recruitment promotes early and robust inflammation in the meninges in EAE. J Autoimmun 42:50–61

    Article  CAS  PubMed  Google Scholar 

  104. Howell OW, Schulz-Trieglaff EK, Carassiti D, Gentleman SM, Nicholas R, Roncaroli F, Reynolds R (2014) Extensive grey matter pathology in the cerebellum in multiple sclerosis is linked to inflammation in the subarachnoid space. Neuropathol Appl Neurobiol. doi: 10.1111/nan.12199

  105. Fabriek BO, Van Haastert ES, Galea I, Polfliet MM, Dopp ED, Van Den Heuvel MM, Van Den Berg TK, De Groot CJ, Van Der Valk P, Dijkstra CD (2005) CD163-positive perivascular macrophages in the human CNS express molecules for antigen recognition and presentation. Glia 51:297–305

    Article  PubMed  Google Scholar 

  106. Bartholomaus I, Kawakami N, Odoardi F, Schlager C, Miljkovic D, Ellwart JW, Klinkert WE, Flugel-Koch C, Issekutz TB, Wekerle H, Flugel A (2009) Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions. Nature 462:94–8

    Article  PubMed  CAS  Google Scholar 

  107. Kooi EJ, van Horssen J, Witte ME, Amor S, Bo L, Dijkstra CD, van der Valk P, Geurts JJ (2009) Abundant extracellular myelin in the meninges of patients with multiple sclerosis. Neuropathol Appl Neurobiol 35:283–95

    Article  CAS  PubMed  Google Scholar 

  108. Liddelow SA (2015) Development of the choroid plexus and blood-CSF barrier. Front Neurosci 9:32

    Article  PubMed Central  PubMed  Google Scholar 

  109. Meeker RB, Williams K, Killebrew DA, Hudson LC (2012) Cell trafficking through the choroid plexus. Cell Adh Migr 6:390–6

    Article  PubMed Central  PubMed  Google Scholar 

  110. Schwartz M, Baruch K (2014) The resolution of neuroinflammation in neurodegeneration: leukocyte recruitment via the choroid plexus. EMBO J 33:7–22

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  111. Kunis G, Baruch K, Miller O, Schwartz M (2015) Immunization with a myelin-derived antigen activates the brain’s choroid plexus for recruitment of immunoregulatory cells to the cns and attenuates disease progression in a mouse model of ALS. J Neurosci 35:6381–93

    Article  CAS  PubMed  Google Scholar 

  112. Engelhardt B, Wolburg-Buchholz K, Wolburg H (2001) Involvement of the choroid plexus in central nervous system inflammation. Microsc Res Tech 52:112–29

    Article  CAS  PubMed  Google Scholar 

  113. Axtell RC, Steinman L (2009) Gaining entry to an uninflamed brain. Nat Immunol 10:453–5

    Article  CAS  PubMed  Google Scholar 

  114. Schmitt C, Strazielle N, Ghersi-Egea JF (2012) Brain leukocyte infiltration initiated by peripheral inflammation or experimental autoimmune encephalomyelitis occurs through pathways connected to the CSF-filled compartments of the forebrain and midbrain. J Neuroinflammation 9:187

    Article  PubMed Central  PubMed  Google Scholar 

  115. Clarkson BD, Walker A, Harris M, Rayasam A, Sandor M, Fabry Z (2014) Mapping the accumulation of co-infiltrating CNS dendritic cells and encephalitogenic T cells during EAE. J Neuroimmunol 277:39–49

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Steffen BJ, Breier G, Butcher EC, Schulz M, Engelhardt B (1996) ICAM-1, VCAM-1, and MAdCAM-1 are expressed on choroid plexus epithelium but not endothelium and mediate binding of lymphocytes in vitro. Am J Pathol 148:1819–38

    PubMed Central  CAS  PubMed  Google Scholar 

  117. Wolburg K, Gerhardt H, Schulz M, Wolburg H, Engelhardt B (1999) Ultrastructural localization of adhesion molecules in the healthy and inflamed choroid plexus of the mouse. Cell Tissue Res 296:259–69

    Article  CAS  PubMed  Google Scholar 

  118. Marques F, Sousa JC, Coppola G, Falcao AM, Rodrigues AJ, Geschwind DH, Sousa N, Correia-Neves M, Palha JA (2009) Kinetic profile of the transcriptome changes induced in the choroid plexus by peripheral inflammation. J Cereb Blood Flow Metab 29:921–32

    Article  CAS  PubMed  Google Scholar 

  119. Marques F, Sousa JC, Coppola G, Geschwind DH, Sousa N, Palha JA, Correia-Neves M (2009) The choroid plexus response to a repeated peripheral inflammatory stimulus. BMC Neurosci 10:135

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  120. Murugesan N, Paul D, Lemire Y, Shrestha B, Ge S, Pachter JS (2012) Active induction of experimental autoimmune encephalomyelitis by MOG35-55 peptide immunization is associated with differential responses in separate compartments of the choroid plexus. Fluids Barriers CNS 9:15

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  121. Szmydynger-Chodobska J, Strazielle N, Gandy JR, Keefe TH, Zink BJ, Ghersi-Egea JF, Chodobski A (2012) Posttraumatic invasion of monocytes across the blood-cerebrospinal fluid barrier. J Cereb Blood Flow Metab 32:93–104

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  122. 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 10:514–23

    Article  CAS  PubMed  Google Scholar 

  123. Elhofy A, Depaolo RW, Lira SA, Lukacs NW, Karpus WJ (2009) Mice deficient for CCR6 fail to control chronic experimental autoimmune encephalomyelitis. J Neuroimmunol 213:91–9

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  124. Vercellino M, Votta B, Condello C, Piacentino C, Romagnolo A, Merola A, Capello E, Mancardi GL, Mutani R, Giordana MT, Cavalla P (2008) Involvement of the choroid plexus in multiple sclerosis autoimmune inflammation: a neuropathological study. J Neuroimmunol 199:133–41

    Article  CAS  PubMed  Google Scholar 

  125. Carlin LM, Stamatiades EG, Auffray C, Hanna RN, Glover L, Vizcay-Barrena G, Hedrick CC, Cook HT, Diebold S, Geissmann F (2013) Nr4a1-dependent Ly6C(low) monocytes monitor endothelial cells and orchestrate their disposal. Cell 153:362–75

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  126. Jakubzick C, Gautier EL, Gibbings SL, Sojka DK, Schlitzer A, Johnson TE, Ivanov S, Duan Q, Bala S, Condon T, van Rooijen N, Grainger JR, Belkaid Y, Ma’ayan A, Riches DW, Yokoyama WM, Ginhoux F, Henson PM, Randolph GJ (2013) Minimal differentiation of classical monocytes as they survey steady-state tissues and transport antigen to lymph nodes. Immunity 39:599–610

    Article  CAS  PubMed  Google Scholar 

  127. Stansfield BK, Ingram DA (2015) Clinical significance of monocyte heterogeneity. Clin Transl Med 4:5

    Article  PubMed Central  PubMed  Google Scholar 

  128. Wong KL, Yeap WH, Tai JJ, Ong SM, Dang TM, Wong SC (2012) The three human monocyte subsets: implications for health and disease. Immunol Res 53:41–57

    Article  CAS  PubMed  Google Scholar 

  129. Schmidl C, Renner K, Peter K, Eder R, Lassmann T, Balwierz PJ, Itoh M, Nagao-Sato S, Kawaji H, Carninci P, Suzuki H, Hayashizaki Y, Andreesen R, Hume DA, Hoffmann P, Forrest AR, Kreutz MP, Edinger M, Rehli M (2014) Transcription and enhancer profiling in human monocyte subsets. Blood 123:e90–9

    Article  CAS  PubMed  Google Scholar 

  130. Wong KL, Tai JJ, Wong WC, Han H, Sem X, Yeap WH, Kourilsky P, Wong SC (2011) Gene expression profiling reveals the defining features of the classical, intermediate, and nonclassical human monocyte subsets. Blood 118:e16–31

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  132. 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, e13693

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  133. King IL, Dickendesher TL, Segal BM (2009) Circulating Ly-6C+ myeloid precursors migrate to the CNS and play a pathogenic role during autoimmune demyelinating disease. Blood 113:3190–7

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  134. Ji Q, Castelli L, Goverman JM (2013) MHC class I-restricted myelin epitopes are cross-presented by Tip-DCs that promote determinant spreading to CD8(+) T cells. Nat Immunol 14:254–61

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  135. Kouwenhoven M, Teleshova N, Ozenci V, Press R, Link H (2001) Monocytes in multiple sclerosis: phenotype and cytokine profile. J Neuroimmunol 112:197–205

    Article  CAS  PubMed  Google Scholar 

  136. Miron VE, Franklin RJ (2014) Macrophages and CNS remyelination. J Neurochem 130:165–71

    Article  CAS  PubMed  Google Scholar 

  137. Miller JC, Brown BD, Shay T, Gautier EL, Jojic V, Cohain A, Pandey G, Leboeuf M, Elpek KG, Helft J, Hashimoto D, Chow A, Price J, Greter M, Bogunovic M, Bellemare-Pelletier A, Frenette PS, Randolph GJ, Turley SJ, Merad M (2012) Deciphering the transcriptional network of the dendritic cell lineage. Nat Immunol 13:888–99

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Sarah Brendecke for graphical figure design. MP was supported by the BMBF-funded competence network of multiple sclerosis (KKNMS), the Sobek Foundation, the DFG (SFB 992, SFB 1160, FOR1336, PR 577/8-1), the Fritz-Thyssen Foundation, and the Gemeinnützige Hertie Foundation (GHST).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Marco Prinz.

Additional information

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Brendecke, S.M., Prinz, M. Do not judge a cell by its cover—diversity of CNS resident, adjoining and infiltrating myeloid cells in inflammation. Semin Immunopathol 37, 591–605 (2015). https://doi.org/10.1007/s00281-015-0520-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00281-015-0520-6

Keywords

Navigation