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

Seminars in Immunopathology

Volumn 37, Issue 6, 2015, Pages 591-605

  Brendecke, Stefanie M ^a   Prinz, Marco ^a  

^a UNIVERSITY OF FREIBURG   (Germany)

Author keywords

EAE; Meninges; Microglia; MS; Myeloid cell; Neuroinflammation

Indexed keywords

BETA INTERFERON;

ANTIGEN PRESENTING CELL; AUTOIMMUNITY; BLOOD BRAIN BARRIER; BONE MARROW CELL; CELL ACTIVATION; CELL DIFFERENTIATION; CELL FUNCTION; CELL INFILTRATION; CELL POPULATION; CELL SHAPE; CHOROID PLEXUS; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; HUMAN; IMMUNOCOMPETENT CELL; MENINX; MONOCYTE; MULTIPLE SCLEROSIS; NEUROMODULATION; NONHUMAN; PATHOGENESIS; PHENOTYPE; PRIORITY JOURNAL; PROTEIN FUNCTION; REGULATORY MECHANISM; REMYELINIZATION; REVIEW; SIGNAL TRANSDUCTION; STEM CELL; T LYMPHOCYTE; TISSUE REPAIR; ANIMAL; CENTRAL NERVOUS SYSTEM; CYTOLOGY; IMMUNOLOGY; MICROGLIA; MOUSE; PATHOLOGY;

ANIMALS; ANTIGEN-PRESENTING CELLS; CENTRAL NERVOUS SYSTEM; ENCEPHALOMYELITIS, AUTOIMMUNE, EXPERIMENTAL; HUMANS; MICE; MICROGLIA; MULTIPLE SCLEROSIS; MYELOID CELLS;

EID: 84945459177     PISSN: 18632297     EISSN: 18632300     Source Type: Journal    
DOI: 10.1007/s00281-015-0520-6     Document Type: Review

References (137)

1. Epelman S, Lavine KJ, Randolph GJ (2014) Origin and functions of tissue macrophages. Immunity 41:21–35
2. Randolph GJ (2014) A macrophage revolution-and beyond. Immunol Rev 262:5–8
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
4. Ginhoux F, Jung S (2014) Monocytes and macrophages: developmental pathways and tissue homeostasis. Nat Rev Immunol 14:392–404
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
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
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
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
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
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
11. Dyrna F, Hanske S, Krueger M, Bechmann I (2013) The blood–brain barrier. J Neuroimmune Pharmacol 8:763–73
12. Ousman SS, Kubes P (2012) Immune surveillance in the central nervous system. Nat Neurosci 15:1096–101
13. Goldmann T, Prinz M (2013) Role of microglia in CNS autoimmunity. Clin Dev Immunol 2013:208093
14. Prinz M, Tay TL, Wolf Y, Jung S (2014) Microglia: unique and common features with other tissue macrophages. Acta Neuropathol 128:319–31
15. Saijo K, Glass CK (2011) Microglial cell origin and phenotypes in health and disease. Nat Rev Immunol 11:775–87
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
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
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
19. Bogie JF, Stinissen P, Hendriks JJ (2014) Macrophage subsets and microglia in multiple sclerosis. Acta Neuropathol 128:191–213
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
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
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
23. Hafler DA (2004) Multiple sclerosis. J Clin Invest 113:788–94
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
25. Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG (2000) Multiple sclerosis. N Engl J Med 343:938–52
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
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
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
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
30. Simmons SB, Pierson ER, Lee SY, Goverman JM (2013) Modeling the heterogeneity of multiple sclerosis in animals. Trends Immunol 34:410–22
31. Stromnes IM, Goverman JM (2006) Passive induction of experimental allergic encephalomyelitis. Nat Protoc 1:1952–60
32. Stromnes IM, Goverman JM (2006) Active induction of experimental allergic encephalomyelitis. Nat Protoc 1:1810–9
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
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
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
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
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
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
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
40. Pinto AR, Godwin JW, Rosenthal NA (2014) Macrophages in cardiac homeostasis, injury responses and progenitor cell mobilisation. Stem Cell Res 13:705–14
41. Gertig U, Hanisch UK (2014) Microglial diversity by responses and responders. Front Cell Neurosci 8:101
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
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
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
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
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
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
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
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
50. Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314–8
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
52. Tremblay ME, Lowery RL, Majewska AK (2010) Microglial interactions with synapses are modulated by visual experience. PLoS Biol 8, e1000527
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
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
55. Benveniste EN (1997) Role of macrophages/microglia in multiple sclerosis and experimental allergic encephalomyelitis. J Mol Med (Berl) 75:165–73
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
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
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
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
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
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
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
64. Hanisch UK (2002) Microglia as a source and target of cytokines. Glia 40:140–55
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
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
67. Bettelli E, Korn T, Oukka M, Kuchroo VK (2008) Induction and effector functions of T(H)17 cells. Nature 453:1051–7
68. Jiang Z, Jiang JX, Zhang GX (2014) Macrophages: a double-edged sword in experimental autoimmune encephalomyelitis. Immunol Lett 160:17–22
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
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
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
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
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
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
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
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
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
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
80. Neumann H, Kotter MR, Franklin RJ (2009) Debris clearance by microglia: an essential link between degeneration and regeneration. Brain 132:288–95
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
82. Cash E, Zhang Y, Rott O (1993) Microglia present myelin antigens to T cells after phagocytosis of oligodendrocytes. Cell Immunol 147:129–38
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
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
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
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
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
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
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
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
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
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
93. Wieghofer P, Knobeloch KP, Prinz M (2015) Genetic targeting of microglia. Glia 63:1–22
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
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
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
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
98. Prineas JW, Wright RG (1978) Macrophages, lymphocytes, and plasma cells in the perivascular compartment in chronic multiple sclerosis. Lab Invest 38:409–21
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
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
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
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
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
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
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
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
108. Liddelow SA (2015) Development of the choroid plexus and blood-CSF barrier. Front Neurosci 9:32
109. Meeker RB, Williams K, Killebrew DA, Hudson LC (2012) Cell trafficking through the choroid plexus. Cell Adh Migr 6:390–6
110. Schwartz M, Baruch K (2014) The resolution of neuroinflammation in neurodegeneration: leukocyte recruitment via the choroid plexus. EMBO J 33:7–22
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
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
113. Axtell RC, Steinman L (2009) Gaining entry to an uninflamed brain. Nat Immunol 10:453–5
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
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
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
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
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
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
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
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
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
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
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
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
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
127. Stansfield BK, Ingram DA (2015) Clinical significance of monocyte heterogeneity. Clin Transl Med 4:5
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
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
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
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
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
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
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
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
136. Miron VE, Franklin RJ (2014) Macrophages and CNS remyelination. J Neurochem 130:165–71
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