Abstract
The diseased brain hosts a heterogeneous population of myeloid cells, including parenchymal microglia, perivascular cells, meningeal macrophages and blood-borne monocytes. To date, the different types of brain myeloid cells have been discriminated solely on the basis of their localization, morphology and surface epitope expression. However, recent data suggest that resident microglia may be functionally distinct from bone marrow– or blood-derived phagocytes, which invade the CNS under pathological conditions. During the last few years, research on brain myeloid cells has been markedly changed by the advent of new tools in imaging, genetics and immunology. These methodologies have yielded unexpected results, which challenge the traditional view of brain macrophages. On the basis of these new studies, we differentiate brain myeloid subtypes with regard to their origin, function and fate in the brain and illustrate the divergent features of these cells during neurodegeneration.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Ransohoff, R.M. & Cardona, A.E. The myeloid cells of the central nervous system parenchyma. Nature 468, 253–262 (2010).
Prinz, M. & Mildner, A. Microglia in the CNS: immigrants from another world. Glia 59, 177–187 (2011).
Geissmann, F. et al. Development of monocytes, macrophages, and dendritic cells. Science 327, 656–661 (2010).
Geissmann, F., Jung, S. & Littman, D.R. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19, 71–82 (2003).
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).
King, I.L., Dickendesher, T.L. & Segal, B.M. Circulating Ly-6C+ myeloid precursors migrate to the CNS and play a pathogenic role during autoimmune demyelinating disease. Blood 113, 3190–3197 (2009).
Mildner, A. et al. CCR2+Ly-6Chi monocytes are crucial for the effector phase of autoimmunity in the central nervous system. Brain 132, 2487–2500 (2009).
Davalos, D. et al. ATP mediates rapid microglial response to local brain injury in vivo. Nat. Neurosci. 8, 752–758 (2005).
Nimmerjahn, A., Kirchhoff, F. & Helmchen, F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 1314–1318 (2005).
Tremblay, M.È., Lowery, R.L. & Majewska, A.K. Microglial interactions with synapses are modulated by visual experience. PLoS Biol. 8, e1000527 (2010).
Roumier, A. et al. Impaired synaptic function in the microglial KARAP/DAP12-deficient mouse. J. Neurosci. 24, 11421–11428 (2004).
Marín-Teva, J.L. et al. Microglia promote the death of developing Purkinje cells. Neuron 41, 535–547 (2004).
Mildner, A. et al. Microglia in the adult brain arise from Ly-6Chi CCR2+ monocytes only under defined host conditions. Nat. Neurosci. 10, 1544–1553 (2007).
Priller, J. et al. Targeting gene-modified hematopoietic cells to the central nervous system: use of green fluorescent protein uncovers microglial engraftment. Nat. Med. 7, 1356–1361 (2001).
Simard, A.R., Soulet, D., Gowing, G., Julien, J.P. & Rivest, S. Bone marrow–derived microglia play a critical role in restricting senile plaque formation in Alzheimer's disease. Neuron 49, 489–502 (2006).
Ashwell, K. The distribution of microglia and cell death in the fetal rat forebrain. Brain Res. Dev. Brain Res. 58, 1–12 (1991).
Alliot, F., Godin, I. & Pessac, B. Microglia derive from progenitors, originating from the yolk sac, and which proliferate in the brain. Brain Res. Dev. Brain Res. 117, 145–152 (1999).
Lichanska, A.M. & Hume, D.A. Origins and functions of phagocytes in the embryo. Exp. Hematol. 28, 601–611 (2000).
Cuadros, M.A. & Navascues, J. The origin and differentiation of microglial cells during development. Prog. Neurobiol. 56, 173–189 (1998).
Beers, D.R. et al. Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis. Proc. Natl. Acad. Sci. USA 103, 16021–16026 (2006).
Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010).
Engelhardt, B. Immune cell entry into the central nervous system: involvement of adhesion molecules and chemokines. J. Neurol. Sci. 274, 23–26 (2008).
Daneman, R., Zhou, L., Kebede, A.A. & Barres, B.A. Pericytes are required for blood-brain barrier integrity during embryogenesis. Nature 468, 562–566 (2010).
Armulik, A. et al. Pericytes regulate the blood-brain barrier. Nature 468, 557–561 (2010).
Bell, R.D. et al. Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron 68, 409–427 (2010).
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).
Unger, E.R. et al. Male donor-derived cells in the brains of female sex-mismatched bone marrow transplant recipients: a Y-chromosome specific in situ hybridization study. J. Neuropathol. Exp. Neurol. 52, 460–470 (1993).
Solomon, J.N. et al. Origin and distribution of bone marrow–derived cells in the central nervous system in a mouse model of amyotrophic lateral sclerosis. Glia 53, 744–753 (2006).
Malm, T.M. et al. Bone-marrow-derived cells contribute to the recruitment of microglial cells in response to beta-amyloid deposition in APP/PS1 double transgenic Alzheimer mice. Neurobiol. Dis. 18, 134–142 (2005).
Priller, J. et al. Early and rapid engraftment of bone marrow–derived microglia in scrapie. J. Neurosci. 26, 11753–11762 (2006).
Djukic, M. et al. Circulating monocytes engraft in the brain, differentiate into microglia and contribute to the pathology following meningitis in mice. Brain 129, 2394–2403 (2006).
Massengale, M., Wagers, A.J., Vogel, H. & Weissman, I.L. Hematopoietic cells maintain hematopoietic fates upon entering the brain. J. Exp. Med. 201, 1579–1589 (2005).
Ajami, B., Bennett, J.L., Krieger, C., Tetzlaff, W. & Rossi, F.M. Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat. Neurosci. 10, 1538–1543 (2007).
Querfurth, H.W. & LaFerla, F.M. Alzheimer's disease. N. Engl. J. Med. 362, 329–344 (2010).
Hardy, J. & Selkoe, D.J. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297, 353–356 (2002).
LaFerla, F.M. Pathways linking Aβ and tau pathologies. Biochem. Soc. Trans. 38, 993–995 (2010).
Corneveaux, J.J. et al. Association of CR1, CLU and PICALM with Alzheimer's disease in a cohort of clinically characterized and neuropathologically verified individuals. Hum. Mol. Genet. 19, 3295–3301 (2010).
Lambert, J.C. et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat. Genet. 41, 1094–1099 (2009).
in t' Veld, B.A. et al. Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease. N. Engl. J. Med. 345, 1515–1521 (2001).
Firuzi, O. & Pratico, D. Coxibs and Alzheimer's disease: should they stay or should they go? Ann. Neurol. 59, 219–228 (2006).
Heneka, M.T., O'Banion, M.K., Terwel, D. & Kummer, M.P. Neuroinflammatory processes in Alzheimer's disease. J. Neural Transm. 117, 919–947 (2010).
Schwab, C., Klegeris, A. & McGeer, P.L. Inflammation in transgenic mouse models of neurodegenerative disorders. Biochim. Biophys. Acta 1802, 889–902 (2010).
Stalder, A.K. et al. Invasion of hematopoietic cells into the brain of amyloid precursor protein transgenic mice. J. Neurosci. 25, 11125–11132 (2005).
Stalder, M., Deller, T., Staufenbiel, M. & Jucker, M. 3D-reconstruction of microglia and amyloid in APP23 transgenic mice: no evidence of intracellular amyloid. Neurobiol. Aging 22, 427–434 (2001).
El Khoury, J. et al. Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat. Med. 13, 432–438 (2007).
Grathwohl, S.A. et al. Formation and maintenance of Alzheimer's disease beta-amyloid plaques in the absence of microglia. Nat. Neurosci. 12, 1361–1363 (2009).
Mildner, A.A. et al. Distinct and nonredundant roles of microglia and myeloid subsets in mouse models of Alzheimer's disease. J. Neurosci. 31, 11159–11171 (2011).
Hawkes, C.A. & McLaurin, J. Selective targeting of perivascular macrophages for clearance of beta-amyloid in cerebral amyloid angiopathy. Proc. Natl. Acad. Sci. USA 106, 1261–1266 (2009).
Sun, B. et al. Cystatin C-cathepsin B axis regulates amyloid beta levels and associated neuronal deficits in an animal model of Alzheimer's disease. Neuron 60, 247–257 (2008).
Mueller-Steiner, S. et al. Antiamyloidogenic and neuroprotective functions of cathepsin B: implications for Alzheimer's disease. Neuron 51, 703–714 (2006).
Mawuenyega, K.G. et al. Decreased clearance of CNS beta-amyloid in Alzheimer's disease. Science 330, 1774 (2010).
Wilcock, D.M. et al. Passive amyloid immunotherapy clears amyloid and transiently activates microglia in a transgenic mouse model of amyloid deposition. J. Neurosci. 24, 6144–6151 (2004).
Koenigsknecht-Talboo, J. et al. Rapid microglial response around amyloid pathology after systemic anti-Abeta antibody administration in PDAPP mice. J. Neurosci. 28, 14156–14164 (2008).
Saederup, N. et al. Selective chemokine receptor usage by central nervous system myeloid cells in CCR2–red fluorescent protein knock-in mice. PLoS ONE 5, e13693 (2010).
Hanisch, U.K. & Kettenmann, H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat. Neurosci. 10, 1387–1394 (2007).
Cardona, A.E. et al. Control of microglial neurotoxicity by the fractalkine receptor. Nat. Neurosci. 9, 917–924 (2006).
Ransohoff, R.M. Chemokines and chemokine receptors: standing at the crossroads of immunobiology and neurobiology. Immunity 31, 711–721 (2009).
Chapman, G.A. et al. Fractalkine cleavage from neuronal membranes represents an acute event in the inflammatory response to excitotoxic brain damage. J. Neurosci. 20, RC87 (2000).
Ransohoff, R.M. & Perry, V.H. Microglial physiology: unique stimuli, specialized responses. Annu. Rev. Immunol. 27, 119–145 (2009).
Fuhrmann, M. et al. Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer's disease. Nat. Neurosci. 13, 411–413 (2010).
Lee, S. et al. CX3CR1 deficiency alters microglial activation and reduces beta-amyloid deposition in two Alzheimer's disease mouse models. Am. J. Pathol. 177, 2549–2562 (2010).
Liu, Z., Condello, C., Schain, A., Harb, R. & Grutzendler, J. CX3CR1 in microglia regulates brain amyloid deposition through selective protofibrillar amyloid-beta phagocytosis. J. Neurosci. 30, 17091–17101 (2010).
Shaftel, S.S. et al. Sustained hippocampal IL-1 beta overexpression mediates chronic neuroinflammation and ameliorates Alzheimer plaque pathology. J. Clin. Invest. 117, 1595–1604 (2007).
Bhaskar, K. et al. Regulation of tau pathology by the microglial fractalkine receptor. Neuron 68, 19–31 (2010).
Schulz, M. & Engelhardt, B. The circumventricular organs participate in the immunopathogenesis of experimental autoimmune encephalomyelitis. Cerebrospinal Fluid Res. 2, 8 (2005).
Nadeau, S. & Rivest, S. Role of microglial-derived tumor necrosis factor in mediating CD14 transcription and nuclear factor kappa B activity in the brain during endotoxemia. J. Neurosci. 20, 3456–3468 (2000).
Perry, V.H., Nicoll, J.A. & Holmes, C. Microglia in neurodegenerative disease. Nat. Rev. Neurol. 6, 193–201 (2010).
Holmes, C. et al. Systemic infection, interleukin 1beta, and cognitive decline in Alzheimer's disease. J. Neurol. Neurosurg. Psychiatry 74, 788–789 (2003).
Price, D.L. et al. The value of transgenic models for the study of neurodegenerative diseases. Ann. NY Acad. Sci. 920, 179–191 (2000).
Choi, S.H. et al. Non-cell-autonomous effects of presenilin 1 variants on enrichment-mediated hippocampal progenitor cell proliferation and differentiation. Neuron 59, 568–580 (2008).
McKercher, S.R. et al. Targeted disruption of the PU.1 gene results in multiple hematopoietic abnormalities. EMBO J. 15, 5647–5658 (1996).
Boillée, S. et al. Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312, 1389–1392 (2006).
Gowing, G., Lalancette-Hebert, M., Audet, J.N., Dequen, F. & Julien, J.P. Macrophage colony stimulating factor (M-CSF) exacerbates ALS disease in a mouse model through altered responses of microglia expressing mutant superoxide dismutase. Exp. Neurol. 220, 267–275 (2009).
Appel, S.H. et al. Hematopoietic stem cell transplantation in patients with sporadic amyotrophic lateral sclerosis. Neurology 71, 1326–1334 (2008).
Gu, X. et al. Pathological cell-cell interactions are necessary for striatal pathogenesis in a conditional mouse model of Huntington's disease. Mol. Neurodegener. 2, 8 (2007).
Giorgini, F., Guidetti, P., Nguyen, Q., Bennett, S.C. & Muchowski, P.J. A genomic screen in yeast implicates kynurenine 3-monooxygenase as a therapeutic target for Huntington disease. Nat. Genet. 37, 526–531 (2005).
Thevandavakkam, M.A., Schwarcz, R., Muchowski, P.J. & Giorgini, F. Targeting kynurenine 3-monooxygenase (KMO): implications for therapy in Huntington's disease. CNS Neurol. Disord. Drug Targets 9, 791–800 (2010).
Björkqvist, M. et al. A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington's disease. J. Exp. Med. 205, 1869–1877 (2008).
Lobsiger, C.S. & Cleveland, D.W. Glial cells as intrinsic components of non–cell autonomous neurodegenerative disease. Nat. Neurosci. 10, 1355–1360 (2007).
McGeer, P.L., Itagaki, S., Boyes, B.E. & McGeer, E.G. Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson's and Alzheimer's disease brains. Neurology 38, 1285–1291 (1988).
Hunot, S. et al. FcepsilonRII/CD23 is expressed in Parkinson's disease and induces, in vitro, production of nitric oxide and tumor necrosis factor-alpha in glial cells. J. Neurosci. 19, 3440–3447 (1999).
Gerhard, A. et al. In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson's disease. Neurobiol. Dis. 21, 404–412 (2006).
Polymeropoulos, M.H. et al. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 276, 2045–2047 (1997).
Zhang, W. et al. Aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson's disease. FASEB J. 19, 533–542 (2005).
Liberatore, G.T. et al. Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease. Nat. Med. 5, 1403–1409 (1999).
Wu, D.C. et al. NADPH oxidase mediates oxidative stress in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease. Proc. Natl. Acad. Sci. USA 100, 6145–6150 (2003).
McCoy, M.K. et al. Blocking soluble tumor necrosis factor signaling with dominant-negative tumor necrosis factor inhibitor attenuates loss of dopaminergic neurons in models of Parkinson's disease. J. Neurosci. 26, 9365–9375 (2006).
Chen, H. et al. Nonsteroidal antiinflammatory drug use and the risk for Parkinson's disease. Ann. Neurol. 58, 963–967 (2005).
Shoji, H., Watanabe, M., Itoh, S., Kuwahara, H. & Hattori, F. Japanese encephalitis and parkinsonism. J. Neurol. 240, 59–60 (1993).
Kokovay, E. & Cunningham, L.A. Bone marrow–derived microglia contribute to the neuroinflammatory response and express iNOS in the MPTP mouse model of Parkinson's disease. Neurobiol. Dis. 19, 471–478 (2005).
Rodriguez, M. et al. Bone marrow–derived cell differentiation into microglia: a study in a progressive mouse model of Parkinson's disease. Neurobiol. Dis. 28, 316–325 (2007).
Keshet, G.I. et al. Increased host neuronal survival and motor function in BMT Parkinsonian mice: involvement of immunosuppression. J. Comp. Neurol. 504, 690–701 (2007).
Biju, K. et al. Macrophage-mediated GDNF delivery protects against dopaminergic neurodegeneration: a therapeutic strategy for Parkinson's disease. Mol. Ther. 18, 1536–1544 (2010).
Klünemann, H.H. et al. The genetic causes of basal ganglia calcification, dementia, and bone cysts: DAP12 and TREM2. Neurology 64, 1502–1507 (2005).
Bechmann, I. et al. Turnover of rat brain perivascular cells. Exp. Neurol. 168, 242–249 (2001).
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).
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).
Auffray, C. et al. Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science 317, 666–670 (2007).
Acknowledgements
The authors wish to thank F.F. Klett for Figure 1, K. Bhaskar and B. Lamb for Figure 2, and K. Kierdorf for fruitful discussion. M.P. was supported by the BMBF-funded Competence Network of Multiple Sclerosis (KKNMS), the Competence Network of Neurodegenerative Disorders (DZNE), the Centre of Chronic Immunodeficiency, the Centre for Biological Signaling Studies, the DFG (SFB 620, FOR1336) and the Hertie-Foundation (Gemeinnützige Hertie-Stiftung). J.P. was supported by the BMBF (Berlin-Brandenburger Center für Regenerative Therapien) and the Deutsche Forschungsgemeinschaft (SFB-TRR43, FOR1336 and the excellence cluster NeuroCure). Research in the S.S.S. laboratory is supported by the National Institutes on Aging, the Adler Foundation and Cure Alzheimer's Fund. The R.M.R. laboratory is supported by the US National Institutes of Health, the National Multiple Sclerosis Society, the Williams Family Fund for Multiple Sclerosis Research and the Nancy Davis Center Without Walls.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Text and Figures
Supplementary Glossary (PDF 21 kb)
Rights and permissions
About this article
Cite this article
Prinz, M., Priller, J., Sisodia, S. et al. Heterogeneity of CNS myeloid cells and their roles in neurodegeneration. Nat Neurosci 14, 1227–1235 (2011). https://doi.org/10.1038/nn.2923
Published:
Issue Date:
DOI: https://doi.org/10.1038/nn.2923
This article is cited by
-
Border-associated macrophages in the central nervous system
Journal of Neuroinflammation (2024)
-
The niche matters: origin, function and fate of CNS-associated macrophages during health and disease
Acta Neuropathologica (2024)
-
Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy
Nature (2023)
-
Near-infrared-IIb emitting single-atom catalyst for imaging-guided therapy of blood-brain barrier breakdown after traumatic brain injury
Nature Communications (2023)
-
Role of Atractylenolide I in Cerebral Ischemia Reperfusion Injury
Revista Brasileira de Farmacognosia (2023)