Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Macrophages at CNS interfaces: ontogeny and function in health and disease

Abstract

The segregation and limited regenerative capacity of the CNS necessitate a specialized and tightly regulated resident immune system that continuously guards the CNS against invading pathogens and injury. Immunity in the CNS has generally been attributed to neuron-associated microglia in the parenchyma, whose origin and functions have recently been elucidated. However, there are several other specialized macrophage populations at the CNS borders, including dural, leptomeningeal, perivascular and choroid plexus macrophages (collectively known as CNS-associated macrophages (CAMs)), whose origins and roles in health and disease have remained largely uncharted. CAMs are thought to be involved in regulating the fine balance between the proper segregation of the CNS, on the one hand, and the essential exchange between the CNS parenchyma and the periphery, on the other. Recent studies that have been empowered by major technological advances have shed new light on these cells and suggest central roles for CAMs in CNS physiology and in the pathogenesis of diseases.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Resident tissue macrophage populations at CNS interfaces.
Fig. 2: Timeline of the discovery of CNS-associated macrophages (CAMs).
Fig. 3: Development and maintenance of CNS-associated macrophages (CAMs).
Fig. 4: CNS-associated macrophage (CAM) diversity.
Fig. 5: CNS-associated macrophages (CAMs) in neurodegeneration and neuroinflammation.

References

  1. Fitch, M. T. & Silver, J. CNS injury, glial scars, and inflammation: inhibitory extracellular matrices and regeneration failure. Exp. Neurol. 209, 294–301 (2008).

    CAS  PubMed  Google Scholar 

  2. Ransohoff, R. M. & Brown, M. A. Innate immunity in the central nervous system. J. Clin. Invest. 122, 1164–1171 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Kierdorf, K. & Prinz, M. Microglia in steady state. J. Clin. Invest. 127, 3201–3209 (2017).

    PubMed  PubMed Central  Google Scholar 

  4. Li, Q. & Barres, B. A. Microglia and macrophages in brain homeostasis and disease. Nat. Rev. Immunol. 18, 225–242 (2018).

    CAS  PubMed  Google Scholar 

  5. Galea, I., Bechmann, I. & Perry, V. H. What is immune privilege (not)? Trends Immunol. 28, 12–18 (2007).

    CAS  PubMed  Google Scholar 

  6. Niederkorn, J. Y. See no evil, hear no evil, do no evil: the lessons of immune privilege. Nat. Immunol. 7, 354–359 (2006).

    CAS  PubMed  Google Scholar 

  7. Engelhardt, B. Regulation of immune cell entry into the central nervous system. Results Probl. Cell Differ. 43, 259–280 (2006).

    CAS  PubMed  Google Scholar 

  8. Absinta, M. et al. Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI. eLife 6, e29738 (2017).

    PubMed  PubMed Central  Google Scholar 

  9. Aspelund, A. et al. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J. Exp. Med. 212, 991–999 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Louveau, A. et al. Structural and functional features of central nervous system lymphatic vessels. Nature 523, 337–341 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Louveau, A. et al. Understanding the functions and relationships of the glymphatic system and meningeal lymphatics. J. Clin. Invest. 127, 3210–3219 (2017).

    PubMed  PubMed Central  Google Scholar 

  12. Raper, D., Louveau, A. & Kipnis, J. How do meningeal lymphatic vessels drain the CNS? Trends Neurosci. 39, 581–586 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Furukawa, M., Shimoda, H., Kajiwara, T., Kato, S. & Yanagisawa, S. Topographic study on nerve-associated lymphatic vessels in the murine craniofacial region by immunohistochemistry and electron microscopy. Biomed. Res. 29, 289–296 (2008).

    CAS  PubMed  Google Scholar 

  14. Gausas, R. E., Daly, T. & Fogt, F. D2-40 expression demonstrates lymphatic vessel characteristics in the dural portion of the optic nerve sheath. Ophthalmic Plast. Reconstr. Surg. 23, 32–36 (2007).

    PubMed  Google Scholar 

  15. Mascagni, P. Vasorum Lymphaticorum Corporis Humani Historia et Ichnographia (P. Carli, 1787).

  16. Andres, K. H., von Düring, M., Muszynski, K. & Schmidt, R. F. Nerve fibres and their terminals of the dura mater encephali of the rat. Anat. Embryol. 175, 289–301 (1987).

    CAS  Google Scholar 

  17. Daneman, R. & Prat, A. The blood–brain barrier. Cold Spring Harb. Perspect. Biol. 7, a020412 (2015).

    PubMed  PubMed Central  Google Scholar 

  18. Erickson, M. A. & Banks, W. A. Neuroimmune axes of the blood–brain barriers and blood–brain interfaces: bases for physiological regulation, disease states, and pharmacological interventions. Pharmacol. Rev. 70, 278–314 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Mrdjen, D. et al. High-dimensional single-cell mapping of central nervous system immune cells reveals distinct myeloid subsets in health, aging, and disease. Immunity 48, 380–395 (2018). This important study investigates CAM heterogeneity at the single-cell level.

    CAS  PubMed  Google Scholar 

  20. Prinz, M., Erny, D. & Hagemeyer, N. Ontogeny and homeostasis of CNS myeloid cells. Nat. Immunol. 18, 385–392 (2017).

    CAS  PubMed  Google Scholar 

  21. Goldmann, T. et al. Origin, fate and dynamics of macrophages at central nervous system interfaces. Nat. Immunol. 17, 797–805 (2016). Goldmann et al. provide the first description of the origin and kinetics of CNS-associated macrophages in the murine CNS.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Jordão, M. J. C. et al. Single-cell profiling identifies myeloid cell subsets with distinct fates during neuroinflammation. Science 363, eaat7554 (2019). This research identifies disease-associated CAM subsets during CNS autoimmunity in mice.

    PubMed  Google Scholar 

  23. Van Hove, H. et al. A single-cell atlas of mouse brain macrophages reveals unique transcriptional identities shaped by ontogeny and tissue environment. Nat. Neurosci. 22, 1021–1035 (2019).

    PubMed  Google Scholar 

  24. McMenamin, P. G., Wealthall, R. J., Deverall, M., Cooper, S. J. & Griffin, B. 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, 259–269 (2003).

    PubMed  Google Scholar 

  25. Schulz, C. et al. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336, 86–90 (2012).

    CAS  PubMed  Google Scholar 

  26. Kierdorf, K. et al. Microglia emerge from erythromyeloid precursors via Pu. 1- and Irf8-dependent pathways. Nat. Neurosci. 16, 273–280 (2013).

    CAS  PubMed  Google Scholar 

  27. Epelman, S. et al. Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation. Immunity 40, 91–104 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Gomez Perdiguero, E. et al. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 518, 547–551 (2015).

    PubMed  Google Scholar 

  29. Hagemeyer, N. et al. Transcriptome-based profiling of yolk sac-derived macrophages reveals a role for Irf8 in macrophage maturation. EMBO J. 35, 1730–1744 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Molawi, K. et al. Progressive replacement of embryo-derived cardiac macrophages with age. J. Exp. Med. 211, 2151–2158 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Mossadegh-Keller, N. et al. Developmental origin and maintenance of distinct testicular macrophage populations. J. Exp. Med. 214, 2829–2841 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Füger, P. et al. Microglia turnover with aging and in an Alzheimer’s model via long-term in vivo single-cell imaging. Nat. Neurosci. 20, 1371–1376 (2017).

    PubMed  Google Scholar 

  33. Tay, T. L. et al. A new fate mapping system reveals context-dependent random or clonal expansion of microglia. Nat. Neurosci. 20, 793–803 (2017). Füger et al. and Tay et al. examine microglia proliferative kinetics in vivo at the single-cell level.

    CAS  PubMed  Google Scholar 

  34. Bechmann, I. et al. Immune surveillance of mouse brain perivascular spaces by blood-borne macrophages. Eur. J. Neurosci. 14, 1651–1658 (2001).

    CAS  PubMed  Google Scholar 

  35. Hickey, W. F., Vass, K. & Lassmann, H. Bone marrow-derived elements in the central nervous system: an immunohistochemical and ultrastructural survey of rat chimeras. J. Neuropathol. Exp. Neurol. 51, 246–256 (1992).

    CAS  PubMed  Google Scholar 

  36. Hickey, W. F. & Kimura, H. Perivascular microglial cells of the CNS are bone marrow-derived and present antigen in vivo. Science 239, 290–292 (1988).

    CAS  PubMed  Google Scholar 

  37. Mildner, A. et al. Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions. Nat. Neurosci. 10, 1544–1553 (2007).

    CAS  PubMed  Google Scholar 

  38. Schilling, M., Strecker, J., Ringelstein, E. B., Kiefer, R. & Schäbitz, W. Turn-over of meningeal and perivascular macrophages in the brain of MCP-1-, CCR-2- or double knockout mice. Exp. Neurol. 219, 583–585 (2009).

    CAS  PubMed  Google Scholar 

  39. Hamann, I. et al. Analyses of phenotypic and functional characteristics of CX3CR1-expressing natural killer cells. Immunology 133, 62–73 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Gerlach, C. et al. The chemokine receptor CX3CR1 defines three antigen-experienced CD8 T cell subsets with distinct roles in immune surveillance and homeostasis. Immunity 45, 1270–1284 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Yona, S. et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38, 79–91 (2013).

    CAS  PubMed  Google Scholar 

  42. Goldmann, T. et al. A new type of microglia gene targeting shows TAK1 to be pivotal in CNS autoimmune inflammation. Nat. Neurosci. 16, 1618–1626 (2013). Yona et al. and Goldmann et al. describe the CX3CR1 ERT2 Cre mouse line, which targets both microglia and CAMs.

    CAS  PubMed  Google Scholar 

  43. Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Stremmel, C. et al. Yolk sac macrophage progenitors traffic to the embryo during defined stages of development. Nat. Commun. 9, 75 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Hashimoto, D. et al. Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 38, 792–804 (2013).

    CAS  PubMed  Google Scholar 

  46. Matyszak, M. K., Lawson, L. J., Perry, V. H. & Gordon, S. Stromal macrophages of the choroid plexus situated at an interface between the brain and peripheral immune system constitutively express major histocompatibility class II antigens. J. Neuroimmunol. 40, 173–181 (1992).

    CAS  PubMed  Google Scholar 

  47. Liddelow, S. A. Development of the choroid plexus and blood-CSF barrier. Front. Neurosci. 9, 1–13 (2015).

    Google Scholar 

  48. Ghersi-Egea, J.-F. et al. Molecular anatomy and functions of the choroidal blood-cerebrospinal fluid barrier in health and disease. Acta Neuropathol. 135, 337–361 (2018).

    CAS  PubMed  Google Scholar 

  49. Bechmann, I. et al. Turnover of rat brain perivascular cells. Exp. Neurol. 168, 242–249 (2001).

    CAS  PubMed  Google Scholar 

  50. Kida, S., Steart, P. V., Zhang, E. T. & Weller, R. O. Perivascular cells act as scavengers in the cerebral perivascular spaces and remain distinct from pericytes, microglia and macrophages. Acta Neuropathol. 85, 646–652 (1993).

    CAS  PubMed  Google Scholar 

  51. Zhang, E. T., Richards, H. K., Kida, S. & Weller, R. O. Directional and compartmentalised drainage of interstitial fluid and cerebrospinal fluid from the rat brain. Acta Neuropathol. 83, 233–239 (1992).

    CAS  PubMed  Google Scholar 

  52. Nayak, D., Zinselmeyer, B. H., Corps, K. N. & McGavern, D. B. In vivo dynamics of innate immune sentinels in the CNS. Intravital 1, 95–106 (2012).

    PubMed  Google Scholar 

  53. Zeisel, A. et al. Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq. Science 347, 1138–1142 (2015). This is the first scRNA-seq study on the rodent CNS, describing the distinct profiles of CAMs versus microglia.

    CAS  PubMed  Google Scholar 

  54. Chinnery, H. R., Ruitenberg, M. J. & McMenamin, P. G. 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 (2010).

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  56. Barkauskas, D. et al. Extravascular CX3CR1+ cells extend intravascular dendritic processes into intact central nervous system vessel lumen. Microsc. Microanal. 19, 778–790 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Schain, A. J. et al. Activation of pial and dural macrophages and dendritic cells by cortical spreading depression. Ann. Neurol. 83, 508–521 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Russo, M. V., Latour, L. L. & McGavern, D. B. Distinct myeloid cell subsets promote meningeal remodeling and vascular repair after mild traumatic brain injury. Nat. Immunol. 19, 442–452 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Ford, A. L. et al. 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, 4309–4321 (1995).

    CAS  PubMed  Google Scholar 

  60. Galea, I. et al. Mannose receptor expression specifically reveals perivascular macrophages in normal, injured, and diseased mouse brain. Glia 49, 375–384 (2005).

    PubMed  Google Scholar 

  61. Ajami, B. et al. Single-cell mass cytometry reveals distinct populations of brain myeloid cells in mouse neuroinflammation and neurodegeneration models. Nat. Neurosci. 21, 541–551 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 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).

    CAS  PubMed  Google Scholar 

  63. Greter, M., Lelios, I. & Croxford, A. L. Microglia versus myeloid cell nomenclature during brain inflammation. Front. Immunol. 6, 249 (2015).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  65. Butovsky, O. et al. Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS. J. Clin. Invest. 122, 3063–3087 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Gingras, M. C., Lapillonne, H. & Margolin, J. F. CFFM4: a new member of the CD20/FcepsilonRIbeta family. Immunogenetics 53, 468–476 (2001).

    CAS  PubMed  Google Scholar 

  67. Mato, M. et al. Involvement of specific macrophage-lineage cells surrounding arterioles in barrier and scavenger function in brain cortex. Proc. Natl Acad. Sci. USA 93, 3269–3274 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Régnier-Vigouroux, A. The mannose receptor in the brain. Int. Rev. Cytol. 226, 321–342 (2003).

    PubMed  Google Scholar 

  69. Kim, W.-K. et al. CD163 identifies perivascular macrophages in normal and viral encephalitic brains and potential precursors to perivascular macrophages in blood. Am. J. Pathol. 168, 822–834 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Rua, R. & McGavern, D. B. Alternatively activated brain-resident macrophages acquire and retain inflammatory properties following CNS infection while interacting with effector and memory T cells. J. Immunol. 196 (Suppl.), 61.17 (2016).

    Google Scholar 

  71. Mesquita, S. D. et al. Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease. Nature 560, 185–191 (2018).

    PubMed  PubMed Central  Google Scholar 

  72. Bechmann, I., Galea, I. & Perry, V. H. What is the blood-brain barrier (not)? Trends Immunol. 28, 5–11 (2007).

    CAS  PubMed  Google Scholar 

  73. Claudio, L., Martiney, J. A. & Brosnan, C. F. Ultrastructural studies of the blood-retina barrier after exposure to interleukin-1 beta or tumor necrosis factor-alpha. Lab. Invest. 70, 850–861 (1994).

    CAS  PubMed  Google Scholar 

  74. He, H. et al. Perivascular macrophages limit permeability. Arterioscler. Thromb. Vasc. Biol. 36, 2203–2212 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Galanternik, M. V. et al. A novel perivascular cell population in the zebrafish brain. eLife 6, e24369 (2017).

    PubMed Central  Google Scholar 

  76. Serrats, J. et al. Dual roles for perivascular macrophages in immune-to-brain signaling. Neuron 65, 94–106 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Matsuwaki, T., Eskilsson, A., Kugelberg, U., Jönsson, J.-I. & Blomqvist, A. Interleukin-1β induced activation of the hypothalamus-pituitary-adrenal axis is dependent on interleukin-1 receptors on non-hematopoietic cells. Brain. Behav. Immun. 40, 166–173 (2014).

    CAS  PubMed  Google Scholar 

  78. Vasilache, A. M., Qian, H. & Blomqvist, A. Immune challenge by intraperitoneal administration of lipopolysaccharide directs gene expression in distinct blood-brain barrier cells toward enhanced prostaglandin E(2) signaling. Brain. Behav. Immun. 48, 31–41 (2015).

    CAS  PubMed  Google Scholar 

  79. Jais, A. et al. Myeloid-cell-derived VEGF maintains brain glucose uptake and limits cognitive impairment in obesity. Cell 165, 882–895 (2016).

    CAS  PubMed  Google Scholar 

  80. Mato, M., Ookawara, S., Sano, M. & Fukuda, S. Uptake of fat by fluorescent granular perithelial cells in cerebral cortex after administration of fat rich chow. Experientia 38, 1496–1498 (1982).

    CAS  PubMed  Google Scholar 

  81. Brück, W. et al. Chapter 14 — macrophages in multiple sclerosis. Immunobiology 195, 588–600 (1996).

    PubMed  Google Scholar 

  82. Walker-Caulfield, M. E., Hatfield, J. K. & Brown, M. A. Dynamic changes in meningeal inflammation correspond to clinical exacerbations in a murine model of relapsing-remitting multiple sclerosis. J. Neuroimmunol. 278, 112–122 (2015).

    CAS  PubMed  Google Scholar 

  83. Ajami, B., Bennett, J. L., Krieger, C., McNagny, K. M. & Rossi, F. M. V. Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nat. Neurosci. 14, 1142–1150 (2011).

    CAS  PubMed  Google Scholar 

  84. Brown, D. A. & Sawchenko, P. E. Time course and distribution of inflammatory and neurodegenerative events suggest structural bases for the pathogenesis of experimental autoimmune encephalomyelitis. J. Comp. Neurol. 260, 236–260 (2007).

    Google Scholar 

  85. Howell, O. W., Carassiti, D., Gentleman, S. M. & Nicholas, R. Extensive grey matter pathology in the cerebellum in multiple sclerosis is linked to inflammation in the subarachnoid space. Neuropathol. Appl. Neurobiol. 41, 798–813 (2015).

    CAS  PubMed  Google Scholar 

  86. Boven, L. A. et al. Myelin-laden macrophages are anti-inflammatory, consistent with foam cells in multiple sclerosis. Brain 129, 517–526 (2006).

    PubMed  Google Scholar 

  87. Greter, M. et al. Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis. Nat. Med. 11, 328–334 (2005).

    CAS  PubMed  Google Scholar 

  88. Prinz, M. & Priller, J. The role of peripheral immune cells in the CNS in steady state and disease. Nat. Neurosci. 20, 136–144 (2017).

    CAS  PubMed  Google Scholar 

  89. Bartholomäus, I. et al. Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions. Nature 462, 94–98 (2009).

    PubMed  Google Scholar 

  90. Schläger, C. et al. Effector T cell trafficking between the leptomeninges and the cerebrospinal fluid. Nature 530, 349–353 (2016).

    PubMed  Google Scholar 

  91. Wolf, Y. et al. Microglial MHC class II is dispensable for experimental autoimmune encephalomyelitis and cuprizone-induced demyelination. Eur. J. Immunol. 48, 1308–1318 (2018).

    CAS  PubMed  Google Scholar 

  92. Mundt, S. et al. Conventional DCs sample and present myelin antigens in the healthy CNS and allow parenchymal T cell entry to initiate neuroinflammation. Sci. Immunol. 4, eaau8380 (2019).

    PubMed  Google Scholar 

  93. Yamasaki, R. et al. Differential roles of microglia and monocytes in the inflamed central nervous system. J. Exp. Med. 211, 1533–1549 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Kooi, E. et al. Abundant extracellular myelin in the meninges of patients with multiple sclerosis. Neuropathol. Appl. Neurobiol. 35, 283–295 (2009).

    CAS  PubMed  Google Scholar 

  95. Heppner, F. L., Ransohoff, R. M. & Becher, B. Immune attack: the role of inflammation in Alzheimer disease. Nat. Rev. Neurosci. 16, 358–372 (2015).

    CAS  PubMed  Google Scholar 

  96. Prinz, M., Priller, J., Sisodia, S. S. & Ransohoff, R. M. Heterogeneity of CNS myeloid cells and their roles in neurodegeneration. Nat. Neurosci. 14, 1227–1235 (2011).

    CAS  PubMed  Google Scholar 

  97. Alonso, A., del, C., Grundke-Iqbal, I. & Iqbal, K. Alzheimer’s disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules. Nat. Med. 2, 783–787 (1996).

    CAS  PubMed  Google Scholar 

  98. Greenberg, S. M. Cerebral amyloid angiopathy and vessel dysfunction. Cerebrovasc. Dis. 13, 42–47 (2002).

    CAS  PubMed  Google Scholar 

  99. Dierksen, G. A. et al. Spatial relation between microbleeds and amyloid deposits in amyloid angiopathy. Ann. Neurol. 68, 545–548 (2010).

    PubMed  PubMed Central  Google Scholar 

  100. Attems, J., Jellinger, K., Thal, D. R. & Van Nostrand, W. Review: sporadic cerebral amyloid angiopathy. Neuropathol. Appl. Neurobiol. 37, 75–93 (2011).

    CAS  PubMed  Google Scholar 

  101. Hawkes, C. A. et al. Perivascular drainage of solutes is impaired in the ageing mouse brain and in the presence of cerebral amyloid angiopathy. Acta Neuropathol. 121, 431–443 (2011).

    PubMed  Google Scholar 

  102. Weller, R. O., Subash, M., Preston, S. D., Mazanti, I. & Carare, R. O. Perivascular drainage of amyloid-beta peptides from the brain and its failure in cerebral amyloid angiopathy and Alzheimer’s disease. Brain Pathol. 18, 253–266 (2008).

    CAS  PubMed  Google Scholar 

  103. Mato, M., Ookawara, S. & Kurihara, K. Uptake of exogenous substances and marked infoldings of the fluorescent granular pericyte in cerebral fine vessels. Am. J. Anat. 157, 329–332 (1980).

    CAS  PubMed  Google Scholar 

  104. Mato, M., Ookawara, S., Aikawa, E. & Kawasaki, K. Studies on fluorescent granular perithelium (F.G.P.) of rat cerebral cortex — especially referring to morphological changes in aging. Anat. Anz. 149, 486–501 (1981).

    CAS  PubMed  Google Scholar 

  105. Mato, M. & Ookawara, S. Influences of age and vasopressin on the uptake capacity of fluorescent granular perithelial cells (FGP) of small cerebral vessels of the rat. Am. J. Anat. 162, 45–53 (1981).

    CAS  PubMed  Google Scholar 

  106. Sasaki, A., Nakazato, Y., Ogawa, A. & Sugihara, S. The immunophenotype of perivascular cells in the human brain. Pathol. Int. 46, 15–23 (1996).

    CAS  PubMed  Google Scholar 

  107. Hawkes, C. A. & McLaurin, J. Selective targeting of perivascular macrophages for clearance of β-amyloid in cerebral amyloid angiopathy. Proc. Natl Acad. Sci. USA 106, 1261–1266 (2009). Hawkes and McLaurin describe evidence of a functional role of CAMs in an Alzheimer disease model.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. El Khoury, J. et al. Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat. Med. 13, 432–438 (2007).

    CAS  PubMed  Google Scholar 

  109. Michaud, J.-P., Bellavance, M.-A., Préfontaine, P. & Rivest, S. Real-time in vivo imaging reveals the ability of monocytes to clear vascular amyloid beta. Cell Rep. 5, 646–653 (2013).

    CAS  PubMed  Google Scholar 

  110. Serbina, N. V. & Pamer, E. G. Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nat. Immunol. 7, 311–317 (2006).

    CAS  PubMed  Google Scholar 

  111. Mildner, A. et al. Distinct and non-redundant roles of microglia and myeloid subsets in mouse models of Alzheimer’s disease. J. Neurosci. 31, 11159–11171 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Park, L. et al. Brain perivascular macrophages initiate the neurovascular dysfunction of Alzheimer Aβ peptides. Circ. Res. 121, 258–269 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Park, L. et al. Scavenger receptor CD36 is essential for the cerebrovascular oxidative stress and neurovascular dysfunction induced by amyloid-beta. Proc. Natl Acad. Sci. USA 108, 5063–5068 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Park, L. et al. Innate immunity receptor CD36 promotes cerebral amyloid angiopathy. Proc. Natl Acad. Sci. USA 110, 3089–3094 (2013).

    PubMed  PubMed Central  Google Scholar 

  115. Thanopoulou, K., Fragkouli, A., Stylianopoulou, F. & Georgopoulos, S. Scavenger receptor class B type I (SR-BI) regulates perivascular macrophages and modifies amyloid pathology in an Alzheimer mouse model. Proc. Natl Acad. Sci. USA 107, 20816–20821 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Kovacs, G. G. et al. Intracellular processing of disease-associated α-synuclein in the human brain suggests prion-like cell-to-cell spread. Neurobiol. Dis. 69, 76–92 (2014).

    CAS  PubMed  Google Scholar 

  117. Liu, Y. et al. Quantitation of perivascular monocytes and macrophages around cerebral blood vessels of hypertensive and aged rats. J. Cereb. Blood Flow Metab. 14, 348–352 (1994).

    CAS  PubMed  Google Scholar 

  118. Zhou, J. et al. CXCR3-dependent accumulation and activation of perivascular macrophages is necessary for homeostatic arterial remodeling to hemodynamic stresses. J. Exp. Med. 207, 1951–1966 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Faraco, G. et al. Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension. J. Clin. Invest. 126, 4674–4689 (2016).

    PubMed  PubMed Central  Google Scholar 

  120. Yu, Y. et al. Brain perivascular macrophages and the sympathetic response to inflammation in rats after myocardial infarction. Hypertension 55, 652–659 (2010).

    CAS  PubMed  Google Scholar 

  121. Pires, P. W. et al. Improvement in middle cerebral artery structure and endothelial function in stroke-prone spontaneously hypertensive rats after macrophage depletion. Microcirculation 20, 650–661 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Pedragosa, J. et al. CNS-border associated macrophages respond to acute ischemic stroke attracting granulocytes and promoting vascular leakage. Acta Neuropathol. Commun. 6, 76 (2018).

    PubMed  PubMed Central  Google Scholar 

  123. Holfelder, K. et al. De novo expression of the hemoglobin scavenger receptor CD163 by activated microglia is not associated with hemorrhages in human brain lesions. Histol. Histopathol. 26, 1007–1017 (2011).

    CAS  PubMed  Google Scholar 

  124. Kristensson, K. Microbes’ roadmap to neurons. Nat. Rev. Neurosci. 12, 345–357 (2011).

    CAS  PubMed  Google Scholar 

  125. Lackner, A. A., Dandekar, S. & Gardner, M. B. Neurobiology of simian and feline immunodeficiency virus infections. Brain Pathol. 1, 201–212 (1991).

    CAS  PubMed  Google Scholar 

  126. Allan, J. E., Dixon, J. E. & Doherty, P. C. Nature of the inflammatory process in the central nervous system of mice infected with lymphocytic choriomeningitis virus. Curr. Top. Microbiol. Immunol. 134, 131–143 (1987).

    CAS  PubMed  Google Scholar 

  127. van den Pol, A. N., Mao, G., Yang, Y., Ornaghi, S. & Davis, J. N. Zika virus targeting in the developing brain. J. Neurosci. 37, 2161–2175 (2017).

    PubMed  PubMed Central  Google Scholar 

  128. Thompson, K. A., Cherry, C. L., Bell, J. E. & McLean, C. A. Brain cell reservoirs of latent virus in presymptomatic HIV-infected individuals. Am. J. Pathol. 179, 1623–1629 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Bragg, D. C. et al. Choroid plexus macrophages proliferate and release toxic factors in response to feline immunodeficiency virus. J. Neurovirol. 8, 225–239 (2002).

    CAS  PubMed  Google Scholar 

  130. Sparger, E. E. et al. Infection of cats with molecularly cloned and biological isolates of the feline immunodeficiency virus. Virology 205, 546–553 (1994).

    CAS  PubMed  Google Scholar 

  131. Joseph, S. B., Arrildt, K. T., Sturdevant, C. B. & Swanstrom, R. HIV-1 target cells in the CNS. J. Neurovirol. 21, 276–289 (2015).

    CAS  PubMed  Google Scholar 

  132. Albright, A. V. et al. Microglia express CCR5, CXCR4, and CCR3, but of these, CCR5 is the principal coreceptor for human immunodeficiency virus type 1 dementia isolates. J. Virol. 73, 205–213 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. González-Scarano, F. & Martín-García, J. The neuropathogenesis of AIDS. Nat. Rev. Immunol. 5, 69–81 (2005).

    PubMed  Google Scholar 

  134. Glass, J. D., Fedor, H., Wesselingh, S. L. & McArthur, J. C. Immunocytochemical quantitation of human immunodeficiency virus in the brain: correlations with dementia. Ann. Neurol. 38, 755–762 (1995).

    CAS  PubMed  Google Scholar 

  135. Kaul, M., Garden, G. A. & Lipton, S. A. Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature 410, 988–994 (2001).

    CAS  PubMed  Google Scholar 

  136. Filipowicz, A. R. et al. Proliferation of perivascular macrophages contributes to the development of encephalitic lesions in HIV-infected humans and in SIV-infected macaques. Sci. Rep. 6, 32900 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. DiNapoli, S. R. et al. Tissue-resident macrophages can contain replication-competent virus in antiretroviral-naive, SIV-infected Asian macaques. JCI Insight 2, e91214 (2017).

    PubMed  PubMed Central  Google Scholar 

  138. Williams, K. C. et al. Perivascular macrophages are the primary cell type productively infected by simian immunodeficiency virus in the brains of macaques. J. Exp. Med. 193, 905–916 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Rua, R. et al. Infection drives meningeal engraftment by inflammatory monocytes that impairs CNS immunity. Nat. Immunol. 20, 407–419 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Steel, C. D. et al. Distinct macrophage subpopulations regulate viral encephalitis but not viral clearance in the CNS. J. Neuroimmunol. 226, 81–92 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Elmquist, J. K. et al. Intravenous lipopolysaccharide induces cyclooxygenase 2-like immunoreactivity in rat brain perivascular microglia and meningeal macrophages. J. Comp. Neurol. 381, 119–129 (1997).

    CAS  PubMed  Google Scholar 

  142. Yamate, J., Ishimine, S., Izawa, T., Kumagai, D. & Kuwamura, M. Macrophage populations and expressions of regulatory proinflammatory factors in the rat meninx under lipopolysaccharide treatment in vivo and in vitro. Histol. Histopathol. 24, 13–24 (2009).

    CAS  PubMed  Google Scholar 

  143. Djukic, M. et al. Circulating monocytes engraft in the brain, differentiate into microglia and contribute to the pathology following meningitis in mice. Brain J. Neurol. 129, 2394–2403 (2006).

    Google Scholar 

  144. Mildner, A. et al. Ly-6G+CCR2 myeloid cells rather than Ly-6ChighCCR2+ monocytes are required for the control of bacterial infection in the central nervous system. J. Immunol. 181, 2713–2722 (2008).

    CAS  PubMed  Google Scholar 

  145. Polfliet, M. M. et al. A method for the selective depletion of perivascular and meningeal macrophages in the central nervous system. J. Neuroimmunol. 116, 188–195 (2001).

    CAS  PubMed  Google Scholar 

  146. Polfliet, M. M. et al. Meningeal and perivascular macrophages of the central nervous system play a protective role during bacterial meningitis. J. Immunol. 167, 4644–4650 (2001).

    CAS  PubMed  Google Scholar 

  147. Trostdorf, F. et al. Reduction of meningeal macrophages does not decrease migration of granulocytes into the CSF and brain parenchyma in experimental pneumococcal meningitis. J. Neuroimmunol. 99, 205–210 (1999).

    CAS  PubMed  Google Scholar 

  148. Nau, R. et al. Granulocytes in the subarachnoid space of humans and rabbits with bacterial meningitis undergo apoptosis and are eliminated by macrophages. Acta Neuropathol. 96, 472–480 (1998).

    CAS  PubMed  Google Scholar 

  149. Masuda, T. et al. Spatial and temporal heterogeneity of mouse and human microglia at single-cell resolution. Nature 566, 388–392 (2019). This article describes the first scRNA-seq study on human microglia during health and neuroinflammation.

    CAS  PubMed  Google Scholar 

  150. Najafi, A. R. et al. A limited capacity for microglial repopulation in the adult brain. Glia 66, 2385–2396 (2018).

    PubMed  PubMed Central  Google Scholar 

  151. Pandya, H. et al. Differentiation of human and murine induced pluripotent stem cells to microglia-like cells. Nat. Neurosci. 20, 753–759 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Muffat, J. et al. Efficient derivation of microglia-like cells from human pluripotent stem cells. Nat. Med. 22, 1358–1367 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Lun, M. P., Monuki, E. S. & Lehtinen, M. K. Development and functions of the choroid plexus–cerebrospinal fluid system. Nat. Rev. Neurosci. 16, 445–457 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Ransohoff, R. M. & Engelhardt, B. The anatomical and cellular basis of immune surveillance in the central nervous system. Nat. Rev. Immunol. 12, 623–635 (2012).

    CAS  PubMed  Google Scholar 

  155. Pollock, H., Hutchings, M., Weller, R. O. & Zhang, E. T. Perivascular spaces in the basal ganglia of the human brain: their relationship to lacunes. J. Anat. 191, 337–346 (1997).

    PubMed  PubMed Central  Google Scholar 

  156. Lam, M. A. et al. The ultrastructure of spinal cord perivascular spaces: implications for the circulation of cerebrospinal fluid. Sci. Rep. 7, 12924 (2017).

    PubMed  PubMed Central  Google Scholar 

  157. Carare, R. O., Hawkes, C. A. & Weller, R. O. Afferent and efferent immunological pathways of the brain. Anatomy, function and failure. Brain. Behav. Immun. 36, 9–14 (2014).

    CAS  PubMed  Google Scholar 

  158. Engelhardt, B. et al. Vascular, glial, and lymphatic immune gateways of the central nervous system. Acta Neuropathol. 132, 317–338 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Weller, R. O. Microscopic morphology and histology of the human meninges. Morphol. Bull. Assoc. Anat. 89, 22–34 (2005).

    CAS  Google Scholar 

  160. Nabeshima, S., Reese, T. S., Landis, D. M. & Brightman, M. W. Junctions in the meninges and marginal glia. J. Comp. Neurol. 164, 127–169 (1975).

    CAS  PubMed  Google Scholar 

  161. Clarke, A. G. The anatomy of the meninges. Postgrad. Med. J. 20, 74–78 (1944).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Wilson, E. H., Weninger, W. & Hunter, C. A. Trafficking of immune cells in the central nervous system. J. Clin. Invest. 120, 1368–1379 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Brocklehurst, G. The significance of the evolution of the cerebrospinal fluid system. Ann. R. Coll. Surg. Engl. 61, 349–356 (1979).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Kappers, C. U. A. The meninges in lower vertebrates compared with those in mammals. Arch. Neurol. Psychiatry 15, 281–296 (1926).

    Google Scholar 

  165. Zajícová, A. Comparative morphology of the meninges of amphibians and reptiles. Folia Morphol. 23, 56–64 (1975).

    Google Scholar 

  166. Butler, A. B. & Hodos, W. Comparative Vertebrate Neuroanatomy: Evolution and Adaptation (John Wiley & Sons, 2005).

  167. Mercier, F., Weatherby, T. M. & Hartline, D. K. Meningeal-like organization of neural tissues in calanoid copepods (Crustacea). J. Comp. Neurol. 521, 760–790 (2013).

    CAS  PubMed  Google Scholar 

  168. Cserr, H. F., Bundgaard, M., Ashby, J. K. & Murray, M. On the anatomic relation of choroid plexus to brain: a comparative study. Am. J. Physiol. 238, R76–R81 (1980).

    CAS  PubMed  Google Scholar 

  169. Abbott, N. J., Lane, N. J. & Bundgaard, M. The blood-brain interface in invertebrates. Ann. NY Acad. Sci. 481, 20–42 (2006).

    Google Scholar 

  170. Soulas, C. et al. Genetically modified CD34+ hematopoietic stem cells contribute to turnover of brain perivascular macrophages in long-term repopulated primates. Am. J. Pathol. 174, 1808–1817 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Fleischhauer, K. Über die Fluoreszenz perivasculärer Zellen im Gehirn der Katze. Z. Zellforsch. Mikrosk. Anat. 64, 140–152 (1964).

    CAS  PubMed  Google Scholar 

  172. Naujoks-Manteuffel, C. & Niemann, U. Microglial cells in the brain of Pleurodeles waltl (Urodela, Salamandridae) after wallerian degeneration in the primary visual system using Bandeiraea simplicifolia isolectin B4-cytochemistry. Glia 10, 101–113 (1994).

    CAS  PubMed  Google Scholar 

  173. Cserr, H. F. & Bundgaard, M. Blood-brain interfaces in vertebrates: a comparative approach. Am. J. Physiol. Regul. Integr. Comp. Physiol. 246, R277–R288 (1984).

    CAS  Google Scholar 

  174. Minagar, A., Ragheb, J. & Kelley, R. E. The Edwin Smith surgical papyrus: description and analysis of the earliest case of aphasia. J. Med. Biogr. 11, 114–117 (2003).

    PubMed  Google Scholar 

  175. Bakay, L. Discovery of the arachnoid membrane. Surg. Neurol. 36, 63–68 (1991).

    CAS  PubMed  Google Scholar 

  176. Dohrmann, G. J. The choroid plexus: a historical review. Brain Res. 18, 197–218 (1970).

    CAS  PubMed  Google Scholar 

  177. Galen, A. Galen on Anatomical Procedures: The Later Books (Cambridge Univ. Press, 2010).

  178. Swanson, L. Neuroanatomical Terminology: A Lexicon of Classical Origins and Historical Foundations (Oxford Univ. Press, 2014).

  179. Wickens, A. P. A History of the Brain: From Stone Age Surgery to Modern Neuroscience (Psychology Press, 2014).

  180. Vesalius, A. De Humani Corporis Fabrica Libri Septem (Johannes Oporinus, 1543).

  181. Liddelow, S. A. Fluids and barriers of the CNS: a historical viewpoint. Fluids Barriers CNS 8, 2 (2011).

    PubMed  PubMed Central  Google Scholar 

  182. Poirier, J. & Derouesné, C. The concept of cerebral lacunae from 1838 to the present [French]. Rev. Neurol. 141, 3–17 (1985).

    CAS  PubMed  Google Scholar 

  183. Deecke, T. On the perivascular spaces in the nervous centers. Am. J. Psychiatry 30, 322–330 (1874).

    Google Scholar 

  184. Obersteiner, H. Über einige Lymphräume im Gehirne. Sitzungsber. Heidelb. Akad. Wiss. Math. Naturwiss. Kl. 61, 57–66 (1870).

    Google Scholar 

  185. Patek, P. R. The perivascular spaces of the mammalian brain. Anat. Rec. 88, 1–24 (1944).

    Google Scholar 

  186. Kubie, L. S. A study of the perivascular tissues of the central nervous system, with the supravital technique. J. Exp. Med. 46, 615–626 (1927).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Rio-Hortega, P. The microglia. Lancet 233, 1023–1026 (1939).

    Google Scholar 

  188. Wislocki, G. B. & Dempsey, E. W. The chemical cytology of the chorioid plexus and blood brain barrier of the rhesus monkey (Macaca mulatta). J. Comp. Neurol. 88, 319–345 (1948).

    CAS  PubMed  Google Scholar 

  189. Mori, S. & Leblond, C. P. Identification of microglia in light and electron microscopy. J. Comp. Neurol. 135, 57–79 (1969).

    CAS  PubMed  Google Scholar 

  190. McLone, D. G. & Bondareff, W. Developmental morphology of the subarachnoid space and contiguous structures in the mouse. Am. J. Anat. 142, 273–293 (1975).

    CAS  PubMed  Google Scholar 

  191. Kivisäkk, P. et al. Localizing CNS immune surveillance: meningeal APCs activate T cells during EAE. Ann. Neurol. 65, 457–469 (2009).

    PubMed  PubMed Central  Google Scholar 

  192. Doran, K. S. et al. Host-pathogen interactions in bacterial meningitis. Acta Neuropathol. 131, 185–209 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. Liu, C. et al. Macrophages mediate the repair of brain vascular rupture through direct physical adhesion and mechanical traction. Immunity 44, 1162–1176 (2016).

    CAS  PubMed  Google Scholar 

  194. Zenaro, E. et al. Neutrophils promote Alzheimer’s disease–like pathology and cognitive decline via LFA-1 integrin. Nat. Med. 21, 880–886 (2015).

    CAS  PubMed  Google Scholar 

  195. Rua, R., Johnson, K. & McGavern, D. B. Discovery of two meningeal macrophage populations with differential roles during homeostasis and inflammation. J. Immunol. 198, 68.6 (2017).

    Google Scholar 

Download references

Acknowledgements

The authors apologize to all those colleagues whose work was discussed without proper citation, owing to space constraints. The authors thank C. Gross and A.G. Peres for excellent help in editing the review. This study was supported by the German Research Foundation (DFG) under Germany’s Excellence Strategy (CIBSS EXC-2189, Project ID 390939984). M.P. is supported by the BMBF (Federal Ministry of Education and Research)-funded competence network of multiple sclerosis (KKNMS), the Sobek Foundation, the Ernst-Jung Foundation, the DFG (SFB 992, SFB1160, SFB/TRR167, Reinhart-Koselleck-Grant) and the Ministry of Science, Research and Arts, Baden-Wuerttemberg (Sonderlinie “Neuroinflammation”).

Author information

Authors and Affiliations

Authors

Contributions

All authors contributed to researching the data for the article and writing the article. M.P. made substantial contributions to discussion of the content of the article and reviewed/edited the article before submission.

Corresponding author

Correspondence to Marco Prinz.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Neuroscience thanks H. Lassmann, S. Rivest and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Microglia

The self-renewing population of tissue macrophages in the CNS parenchyma, which serve a plethora of functions during development and homeostasis and are implicated in many neurodegenerative and neuroimmunological diseases of the CNS.

Lymphatic system

A vasculature system throughout the body that consists of low-pressure vessels that drain interstitial fluid from all organs to the heart and also serve important immune functions by allowing immune cell trafficking between organs, the lymph nodes and the spleen.

Immune surveillance

The constant patrol of circulating and resident immune cells throughout the body and within their host tissue. The cells recognize and eliminate invading pathogens, clean up tissue injuries and remove unwanted host cells, such as cancer cells.

Antigen presentation

An essential immune process in which antigen-presenting cells (such as dendritic cells) trigger adaptive T cell responses against specific antigens by presenting antigen epitopes and co-stimulatory signals on their surface.

Yolk sac

A membranous sac present in most developing vertebrate embryos, which provides the embryo with nutrients by a direct connection via blood vessels and also harbours the blood islands, the specialized region within which the first haematopoietic cells of the embryo arise.

Clonal expansion

The extensive proliferation of a group of identical cells that are originally derived from the same ancestor cell.

Blood–brain barrier

(BBB). A multicellular barrier system that separates the CNS parenchyma from the periphery along CNS interfaces and restricts immune cell migration to the CNS.

Single-cell RNA sequencing

(scRNA-seq). A new, unbiased technology using next-generation sequencing to evaluate the gene expression profile of single cells within a whole tissue or an isolated group of cells.

Astrogliosis

Activation of astrocytes by inflammation, injury or an infection, characterized by extensive proliferation, morphological changes and cytokine secretion.

T helper cells

Specialized CD4+ T cells that are involved in the adaptive immune response. T helper cells are activated and expand upon antigen presentation. They secrete important cytokines to support the immune response of macrophages, B cells and also cytotoxic T cells.

Dendritic cells

Professional antigen-presenting cells of the innate immune system that constantly digest and process antigens and present them to T cells to induce an antigen-specific adaptive immune response.

Induced pluripotent stem cells

An artificially generated type of pluripotent stem cell, produced by the reprogramming of adult differentiated cells with defined factors ex vivo.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kierdorf, K., Masuda, T., Jordão, M.J.C. et al. Macrophages at CNS interfaces: ontogeny and function in health and disease. Nat Rev Neurosci 20, 547–562 (2019). https://doi.org/10.1038/s41583-019-0201-x

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41583-019-0201-x

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing