Advertisement

Journal of Molecular Medicine

, Volume 95, Issue 11, pp 1143–1152 | Cite as

Brain perivascular macrophages: characterization and functional roles in health and disease

  • Giuseppe FaracoEmail author
  • Laibaik Park
  • Josef Anrather
  • Costantino IadecolaEmail author
Review

Abstract

Perivascular macrophages (PVM) are a distinct population of resident brain macrophages characterized by a close association with the cerebral vasculature. PVM migrate from the yolk sac into the brain early in development and, like microglia, are likely to be a self-renewing cell population that, in the normal state, is not replenished by circulating monocytes. Increasing evidence implicates PVM in several disease processes, ranging from brain infections and immune activation to regulation of the hypothalamic-adrenal axis and neurovascular-neurocognitive dysfunction in the setting of hypertension, Alzheimer disease pathology, or obesity. These effects involve crosstalk between PVM and cerebral endothelial cells, interaction with circulating immune cells, and/or production of reactive oxygen species. Overall, the available evidence supports the idea that PVM are a key component of the brain-resident immune system with broad implications for the pathogenesis of major brain diseases. A better understanding of the biology and pathobiology of PVM may lead to new insights and therapeutic strategies for a wide variety of brain diseases.

Keywords

Brain perivascular macrophages Immune-to-brain signaling Alzheimer’s disease Cerebrovascular regulation CNS infections 

Notes

Compliance with ethical standards

Grant support

This work was supported by the following grants: 15SDG22760007 (GF), R01 NS37853, R37 NS89323, and R01 NS100441. Support from the Feil Family Foundation is gratefully acknowledged.

References

  1. 1.
    Engelhardt B, Vajkoczy P, Weller RO (2017) The movers and shapers in immune privilege of the CNS. Nat Immunol 18:123–131CrossRefPubMedGoogle Scholar
  2. 2.
    Herz J, Filiano AJ, Smith A, Yogev N, Kipnis J (2017) Myeloid cells in the central nervous system. Immunity 46:943–956CrossRefPubMedGoogle Scholar
  3. 3.
    Prinz M, Erny D, Hagemeyer N (2017) Ontogeny and homeostasis of CNS myeloid cells. Nat Immunol 18:385–392CrossRefPubMedGoogle Scholar
  4. 4.
    Saijo K, Glass CK (2011) Microglial cell origin and phenotypes in health and disease. Nat Rev Immunol 11:775–787CrossRefPubMedGoogle Scholar
  5. 5.
    Ransohoff RM, Engelhardt B (2012) The anatomical and cellular basis of immune surveillance in the central nervous system. Nat Rev Immunol 12:623–635CrossRefPubMedGoogle Scholar
  6. 6.
    Zhang ET, Inman CB, Weller RO (1990) Interrelationships of the pia mater and the perivascular (Virchow-Robin) spaces in the human cerebrum. J Anat 170:111–123PubMedPubMedCentralGoogle Scholar
  7. 7.
    Galanternik MV, Castranova D, Gore AV, Blewett NH, Jung HM, Stratman AN, Kirby MR, Iben J, Miller MF, Kawakami K et al (2017) A novel perivascular cell population in the zebrafish brain. Elife. doi: 10.7554/eLife.24369
  8. 8.
    Mato M, Ookawara S, Kurihara K (1980) Uptake of exogenous substances and marked infoldings of the fluorescent granular pericyte in cerebral fine vessels. Am J Anat 157:329–332CrossRefPubMedGoogle Scholar
  9. 9.
    Mato M, Aikawa E, Mato TK, Kurihara K (1986) Tridimensional observation of fluorescent granular perithelial (FGP) cells in rat cerebral blood vessels. Anat Rec 215:413–419CrossRefPubMedGoogle Scholar
  10. 10.
    Mato M, Ookawara S, Sano M, Fukuda S (1982) Uptake of fat by fluorescent granular perithelial cells in cerebral cortex after administration of fat rich chow. Experientia 38:1496–1498CrossRefPubMedGoogle Scholar
  11. 11.
    Mato M, Ookawara S, Sakamoto A, Aikawa E, Ogawa T, Mitsuhashi U, Masuzawa T, Suzuki H, Honda M, Yazaki Y et al (1996) Involvement of specific macrophage-lineage cells surrounding arterioles in barrier and scavenger function in brain cortex. Proc Natl Acad Sci U S A 93:3269–3274CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Ookawara S, Mitsuhashi U, Suminaga Y, Mato M (1996) Study on distribution of pericyte and fluorescent granular perithelial (FGP) cell in the transitional region between arteriole and capillary in rat cerebral cortex. Anat Rec 244:257–264CrossRefPubMedGoogle Scholar
  13. 13.
    Hickey WF, Kimura H (1988) Perivascular microglial cells of the CNS are bone marrow-derived and present antigen in vivo. Science 239:290–292CrossRefPubMedGoogle Scholar
  14. 14.
    Graeber MB, Streit WJ, Kreutzberg GW (1989) Identity of ED2-positive perivascular cells in rat brain. J Neurosci Res 22:103–106CrossRefPubMedGoogle Scholar
  15. 15.
    Fabriek BO, Polfliet MMJ, Vloet RPM, van der Schors RC, Ligtenberg AJ, Weaver LK, Geest C, Matsuno K, Moestrup SK, Dijkstra CD et al (2007) The macrophage CD163 surface glycoprotein is an erythroblast adhesion receptor. Blood 109:5223–5229CrossRefPubMedGoogle Scholar
  16. 16.
    Fabriek BO, Van Haastert ES, Galea I, Polfliet MM, Döpp 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 51:297–305CrossRefPubMedGoogle Scholar
  17. 17.
    Kim W-K, Alvarez X, Fisher J, Bronfin B, Westmoreland S, McLaurin J, Williams K (2006) CD163 identifies perivascular macrophages in normal and viral encephalitic brains and potential precursors to perivascular macrophages in blood. Am J Pathol 168:822–834CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Galea I, Palin K, Newman TA, Van Rooijen N, Perry VH, Boche D (2004) Mannose receptor expression specifically reveals perivascular macrophages in normal, injured, and diseased mouse brain. Glia 49:375–384CrossRefGoogle Scholar
  19. 19.
    Faraco G, Sugiyama Y, Lane D, Garcia-Bonilla L, Chang H, Santisteban MM, Racchumi G, Murphy M, Van Rooijen N, Anrather J et al (2016) Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension. J Clin Invest 126:4674–4689CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Linehan SA, Stahl PD, Gordon S (1999) Mannose receptor and its putative ligands in normal murine lymphoid and nonlymphoid organs: in situ expression of mannose receptor by selected macrophages, endothelial cells, perivascular microglia, and mesangial cells, but not dendritic cells. J Exp Med 189:1961–1972CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Linehan SA, Martinez-Pomares L, Gordon S (2000) Mannose receptor and scavenger receptor: two macrophage pattern recognition receptors with diverse functions in tissue homeostasis and host defense. Adv Exp Med Biol 479:1–14PubMedGoogle Scholar
  22. 22.
    Goldmann T, Wieghofer P, Jordão MJC, Prutek F, Hagemeyer N, Frenzel K, Amann L, Staszewski O, Kierdorf K, Krueger M et al (2016) Origin, fate and dynamics of macrophages at central nervous system interfaces. Nat Immunol 17:797–805CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    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 9:716–726CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    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 69:896–909CrossRefPubMedGoogle Scholar
  25. 25.
    Zeisel A, Muñoz-Manchado AB, Codeluppi S, Lönnerberg P, La Manno G, Juréus A, Marques S, Munguba H, He L, Betsholtz C et al (2015) Brain structure. Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq. Science 347:1138–1142CrossRefPubMedGoogle Scholar
  26. 26.
    Bechmann I, Priller J, Kovac A, Böntert M, Wehner T, Klett FF, Bohsung J, Stuschke M, Dirnagl U, Nitsch R (2002) Immune surveillance of mouse brain perivascular spaces by blood-borne macrophages. Eur J Neurosci 14:1651–1658CrossRefGoogle Scholar
  27. 27.
    del Rey A, Balschun D, Wetzel W, Randolf A, Besedovsky HO (2013) A cytokine network involving brain-borne IL-1β, IL-1ra, IL-18, IL-6, and TNFα operates during long-term potentiation and learning. Brain Behav Immun 33:15–23CrossRefPubMedGoogle Scholar
  28. 28.
    Bechmann I, Kwidzinski E, Kovac AD, Simbürger E, Horvath T, Gimsa U, Dirnagl U, Priller J, Nitsch R (2001) Turnover of rat brain perivascular cells. Exp Neurol 168:242–249CrossRefPubMedGoogle Scholar
  29. 29.
    Polfliet MM, Goede PH, van Kesteren-Hendrikx EM, van Rooijen N, Dijkstra CD, van den Berg TK (2001) A method for the selective depletion of perivascular and meningeal macrophages in the central nervous system. J Neuroimmunol 116:188–195CrossRefPubMedGoogle Scholar
  30. 30.
    Lehenkari PP, Kellinsalmi M, Näpänkangas JP, Ylitalo KV, Mönkkönen J, Rogers MJ, Azhayev A, Väänänen HK, Hassinen IE (2002) Further insight into mechanism of action of clodronate: inhibition of mitochondrial ADP/ATP translocase by a nonhydrolyzable, adenine-containing metabolite. Mol Pharmacol 61:1255–1262CrossRefPubMedGoogle Scholar
  31. 31.
    Hickey WF, Vass K, Lassmann H (1992) Bone marrow-derived elements in the central nervous system: an immunohistochemical and ultrastructural survey of rat chimeras. J Neuropathol Exp Neurol 51:246–256CrossRefPubMedGoogle Scholar
  32. 32.
    Vallières L, Sawchenko PE (2003) Bone marrow-derived cells that populate the adult mouse brain preserve their hematopoietic identity. J Neurosci 23:5197–5207PubMedGoogle Scholar
  33. 33.
    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:e58544CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Mildner A, Schmidt H, Nitsche M, Merkler D, Hanisch UK, Mack M, Heikenwalder M, Brück W, Priller J, Prinz M (2007) Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions. Nat Neurosci 10:1544–1553CrossRefPubMedGoogle Scholar
  35. 35.
    Perdiguero EG, Geissmann F (2013) Myb-independent macrophages: a family of cells that develops with their tissue of residence and is involved in its homeostasis. Cold Spring Harb Symp Quant Biol 78:91–100CrossRefGoogle Scholar
  36. 36.
    De Strooper B, Karran E (2016) The cellular phase of Alzheimer’s disease. Cell 164:603–615CrossRefPubMedGoogle Scholar
  37. 37.
    Kida S, Steart PV, Zhang ET, Weller RO (1993) Perivascular cells act as scavengers in the cerebral perivascular spaces and remain distinct from pericytes, microglia and macrophages. Acta Neuropathol 85:646–652CrossRefPubMedGoogle Scholar
  38. 38.
    McLaurin J, Hawkes C (2009) Selective targeting of perivascular macrophages for β-amyloid clearance in cerebral amyloid angiopathy. Alzheimers Dement 5:P152CrossRefGoogle Scholar
  39. 39.
    Thanopoulou K, Fragkouli A, Stylianopoulou F, Georgopoulos S (2010) Scavenger receptor class B type I (SR-BI) regulates perivascular macrophages and modifies amyloid pathology in an Alzheimer mouse model. Proc Natl Acad Sci U S A 107:20816–20821CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Steinberg D (1996) A docking receptor for HDL cholesterol esters. Science 271:460–461CrossRefPubMedGoogle Scholar
  41. 41.
    Mucke L, Masliah E, Yu GQ, Mallory M, Rockenstein EM, Tatsuno G, Hu K, Kholodenko D, Johnson-Wood K et al (2000) High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci 20:4050–4058PubMedGoogle Scholar
  42. 42.
    Iadecola C (2004) Neurovascular regulation in the normal brain and in Alzheimer’s disease. Nat Rev Neurosci 5:347–360CrossRefPubMedGoogle Scholar
  43. 43.
    Park L, Uekawa K, Garcia-Bonilla L, Koizumi K, Murphy M, Pistik R, Younkin L, Younkin S, Zhou P, Carlson G et al (2017) Brain perivascular macrophages initiate the neurovascular dysfunction of Alzheimer Aβ peptides. Circ Res. doi: 10.1161/CIRCRESAHA.117.311054
  44. 44.
    He H, Mack JJ, Güç E, Warren CM, Squadrito ML, Kilarski WW, Baer C, Freshman RD, McDonald AI, Ziyad S et al (2016) Perivascular macrophages limit permeability. Arterioscler Thromb Vasc Biol 36:2203–2212CrossRefPubMedGoogle Scholar
  45. 45.
    Willis CL, Garwood CJ, Ray DE (2007) A size selective vascular barrier in the rat area postrema formed by perivascular macrophages and the extracellular matrix. Neuroscience 150:498–509CrossRefPubMedGoogle Scholar
  46. 46.
    Mendes-Jorge L, Ramos D, Luppo M, Llombart C, Alexandre-Pires G, Nacher V, Melgarejo V, Correia M, Navarro M, Carretero A et al (2009) Scavenger function of resident autofluorescent perivascular macrophages and their contribution to the maintenance of the blood-retinal barrier. Invest Ophthalmol Vis Sci 50:5997–6005CrossRefPubMedGoogle Scholar
  47. 47.
    Polfliet MM, Zwijnenburg PJ, van Furth AM, van der Poll T, Döpp EA, Renardel de Lavalette C, van Kesteren-Hendrikx EM, van Rooijen N, Dijkstra CD, van den Berg TK (2001) Meningeal and perivascular macrophages of the central nervous system play a protective role during bacterial meningitis. J Immunol 167:4644–4650CrossRefPubMedGoogle Scholar
  48. 48.
    Steel CD, Kim W-K, Sanford LD, Wellman LL, Burnett S, Van Rooijen N, Ciavarra RP (2010) Distinct macrophage subpopulations regulate viral encephalitis but not viral clearance in the CNS. J Neuroimmunol 226:81–92CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Williams KC, Hickey WF (2002) Central nervous system damage, monocytes and macrophages, and neurological disorders in AIDS. Annu Rev Neurosci 25:537–562CrossRefPubMedGoogle Scholar
  50. 50.
    Williams KC, Corey S, Westmoreland SV, Pauley D, Knight H, deBakker C, Alvarez X, Lackner AA (2001) Perivascular macrophages are the primary cell type productively infected by simian immunodeficiency virus in the brains of macaques: implications for the neuropathogenesis of AIDS. J Exp Med 193:905–915CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Nowlin BT, Burdo TH, Midkiff CC, Salemi M, Alvarez X, Williams KC (2015) SIV encephalitis lesions are composed of CD163(+) macrophages present in the central nervous system during early SIV infection and SIV-positive macrophages recruited terminally with AIDS. Am J Pathol 185:1649–1665CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Filipowicz AR, McGary CM, Holder GE, Lindgren AA, Johnson EM, Sugimoto C, Kuroda MJ, Kim WK (2016) Proliferation of perivascular macrophages contributes to the development of encephalitic lesions in HIV-infected humans and in SIV-infected macaques. Sci Rep 6:32900CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Zhang Z, Zhang Z-Y, Schittenhelm J, Wu Y, Meyermann R, Schluesener HJ (2011) Parenchymal accumulation of CD163+ macrophages/microglia in multiple sclerosis brains. J Neuroimmunol 237:73–79CrossRefPubMedGoogle Scholar
  54. 54.
    Polfliet MMJ, van de Veerdonk F, Döpp EA, van Kesteren-Hendrikx EM, van Rooijen N, Dijkstra CD, van den Berg TK (2002) The role of perivascular and meningeal macrophages in experimental allergic encephalomyelitis. J Neuroimmunol 122:1–8CrossRefPubMedGoogle Scholar
  55. 55.
    Hofmann N, Lachnit N, Streppel M, Witter B, Neiss WF, Guntinas-Lichius O, Angelov DN (2002) Increased expression of ICAM-1, VCAM-1, MCP-1, and MIP-1 alpha by spinal perivascular macrophages during experimental allergic encephalomyelitis in rats. BMC Immunol 3:11CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Turnbull AV, Rivier CL (1999) Regulation of the hypothalamic-pituitary-adrenal axis by cytokines: actions and mechanisms of action. Physiol Rev 79:1–71PubMedGoogle Scholar
  57. 57.
    Elmquist JK, Breder CD, Sherin JE, Scammell TE, Hickey WF, Dewitt D, Saper CB (1997) Intravenous lipopolysaccharide induces cyclooxygenase 2-like immunoreactivity in rat brain perivascular microglia and meningeal macrophages. J Comp Neurol 381:119–129CrossRefPubMedGoogle Scholar
  58. 58.
    Vasilache AM, Qian H, Blomqvist A (2015) 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 48:31–41CrossRefPubMedGoogle Scholar
  59. 59.
    Serrats J, Schiltz JC, García-Bueno B, van Rooijen N, Reyes TM, Sawchenko PE (2010) Dual roles for perivascular macrophages in immune-to-brain signaling. Neuron 65:94–106CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Schiltz JC, Sawchenko PE (2002) Distinct brain vascular cell types manifest inducible cyclooxygenase expression as a function of the strength and nature of immune insults. J Neurosci 22:5606–5618PubMedGoogle Scholar
  61. 61.
    Serrats J, Grigoleit J-S, Alvarez-Salas E, Sawchenko PE (2017) Pro-inflammatory immune-to-brain signaling is involved in neuroendocrine responses to acute emotional stress. Brain Behav Immun 62:53–63CrossRefPubMedGoogle Scholar
  62. 62.
    Antoni FA (1993) Vasopressinergic control of pituitary adrenocorticotropin secretion comes of age. Front Neuroendocrinol 14:76–122CrossRefPubMedGoogle Scholar
  63. 63.
    Yu Y, Zhang Z-H, Wei S-G, Serrats J, Weiss RM, Felder RB (2010) Brain perivascular macrophages and the sympathetic response to inflammation in rats after myocardial infarction. Hypertension 55:652–659CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Faraco G, Iadecola C (2013) Hypertension: a harbinger of stroke and dementia. Hypertension 62:810–817CrossRefPubMedGoogle Scholar
  65. 65.
    Capone C, Faraco G, Park L, Cao X, Davisson RL, Iadecola C (2010) The cerebrovascular dysfunction induced by slow pressor doses of angiotensin II precedes the development of hypertension. Am J Physiol Heart Circ Physiol 300:H397–H407CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Pires PW, Girgla SS, McClain JL, Kaminski NE, van Rooijen N, Dorrance AM (2013) Improvement in middle cerebral artery structure and endothelial function in stroke-prone spontaneously hypertensive rats after macrophage depletion. Microcirculation 20:650–661CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Schlager G (1981) Longevity in spontaneously hypertensive mice. Exp Gerontol 16:325CrossRefPubMedGoogle Scholar
  68. 68.
    Holfelder K, Schittenhelm J, Trautmann K, Haybaeck J, Meyermann R, Beschorner R (2011) De novo expression of the hemoglobin scavenger receptor CD163 by activated microglia is not associated with hemorrhages in human brain lesions. Histol Histopathol 26:1007–1017PubMedGoogle Scholar
  69. 69.
    Zhang Z, Zhang Z-Y, Wu Y, Schluesener HJ (2012) Lesional accumulation of CD163+ macrophages/microglia in rat traumatic brain injury. Brain Res 1461:102–110CrossRefPubMedGoogle Scholar
  70. 70.
    Jais A, Solas M, Backes H, Chaurasia B, Kleinridders A, Theurich S, Mauer J, Steculorum SM, Hampel B, Goldau J et al (2016) Myeloid-cell-derived VEGF maintains brain glucose uptake and limits cognitive impairment in obesity. Cell 165:882–895CrossRefPubMedGoogle Scholar
  71. 71.
    Tay TL, Mai D, Dautzenberg J, Fernández-Klett F, Lin G, Sagar DM, Drougard A, Stempfl T, Ardura-Fabregat A et al (2017) A new fate mapping system reveals context-dependent random or clonal expansion of microglia. Nat Neurosci 20:793–803CrossRefPubMedGoogle Scholar
  72. 72.
    Kipnis J (2016) Multifaceted interactions between adaptive immunity and the central nervous system. Science 353:766CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, Mehler MF, Conway SJ, Ng LG, Stanley ER et al (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330:841–845CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Kierdorf K, Erny D, Goldmann T, Sander V, Schulz C, Perdiguero EG, Wieghofer P, Heinrich A, Riemke P, Hölscher C et al (2013) Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nat Neurosci 16:273–280CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  1. 1.Feil Family Brain and Mind Research InstituteWeill Cornell MedicineNew YorkUSA

Personalised recommendations