Microglia and macrophages in brain homeostasis and disease

Key Points

  • Microglia arise solely from yolk sac erythromyeloid precursors under normal conditions, although the precise nature of these precursors is controversial.

  • Peripheral cells can infiltrate the central nervous system (CNS) in certain artificial or pathological conditions, but the functional significance of different microglial origins remains elusive.

  • Microglial precursors migrate to the brain parenchyma and quickly diverge from other tissue-resident macrophages, in terms of their gene expression profile, under the influence of unknown brain-derived signals.

  • During homeostasis, microglia maintain steady, region-specific densities by self-renewal.

  • Microglia interact with almost all CNS components during embryonic and postnatal development, when they carry out a large number of non-immune tasks that are crucial for brain function.

  • Microglia have multidimensional activation states in CNS diseases and injuries, such that these cells can have beneficial or detrimental roles depending on the context.


Microglia and non-parenchymal macrophages in the brain are mononuclear phagocytes that are increasingly recognized to be essential players in the development, homeostasis and diseases of the central nervous system. With the availability of new genetic, molecular and pharmacological tools, considerable advances have been made towards our understanding of the embryonic origins, developmental programmes and functions of these cells. These exciting discoveries, some of which are still controversial, also raise many new questions, which makes brain macrophage biology a fast-growing field at the intersection of neuroscience and immunology. Here, we review the current knowledge of how and where brain macrophages are generated, with a focus on parenchymal microglia. We also discuss their normal functions during development and homeostasis, the disturbance of which may lead to various neurodegenerative and neuropsychiatric diseases.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: The microenvironments and genetic signatures for brain macrophages.
Figure 2: Ontogeny and development of microglia and tissue macrophages.
Figure 3: Microglial functions in development and homeostasis.
Figure 4: Microglial functions during CNS injuries and diseases.


  1. 1

    Perez-Cerda, F., Sanchez-Gomez, M. V. & Matute, C. Pio del Rio Hortega and the discovery of the oligodendrocytes. Front. Neuroanat. 9, 92 (2015).

    PubMed  PubMed Central  Google Scholar 

  2. 2

    Ginhoux, F., Lim, S., Hoeffel, G., Low, D. & Huber, T. Origin and differentiation of microglia. Front. Cell. Neurosci. 7, 45 (2013).

    PubMed  PubMed Central  Google Scholar 

  3. 3

    Ginhoux, F. & Guilliams, M. Tissue-resident macrophage ontogeny and homeostasis. Immunity 44, 439–449 (2016).

    CAS  PubMed  Google Scholar 

  4. 4

    Hoeffel, G. & Ginhoux, F. Ontogeny of tissue-resident macrophages. Front. Immunol. 6, 486 (2015).

    PubMed  PubMed Central  Google Scholar 

  5. 5

    Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010). This work uses a novel fate-mapping system to definitively show that microglia arise from YS precursors.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    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).

    CAS  PubMed  Google Scholar 

  7. 7

    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 

  8. 8

    Sheng, J., Ruedl, C. & Karjalainen, K. Most tissue-resident macrophages except microglia are derived from fetal hematopoietic stem cells. Immunity 43, 382–393 (2015).

    CAS  PubMed  Google Scholar 

  9. 9

    Nimmerjahn, A., Kirchhoff, F. & Helmchen, F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 1314–1318 (2005). This in vivo imaging study demonstrates the high motility of microglial processes under homeostasis, which opens new avenues for studying non-immune functions of microglia.

    CAS  Google Scholar 

  10. 10

    Tremblay, M. E., Lowery, R. L. & Majewska, A. K. Microglial interactions with synapses are modulated by visual experience. PLoS Biol. 8, e1000527 (2010).

    PubMed  PubMed Central  Google Scholar 

  11. 11

    Wake, H., Moorhouse, A. J., Jinno, S., Kohsaka, S. & Nabekura, J. Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J. Neurosci. 29, 3974–3980 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Frost, J. L. & Schafer, D. P. Microglia: architects of the developing nervous system. Trends Cell Biol. 26, 587–597 (2016).

    PubMed  PubMed Central  Google Scholar 

  13. 13

    Schafer, D. P. & Stevens, B. Microglia function in central nervous system development and plasticity. Cold Spring Harb. Perspect.Biol. 7, a020545 (2015).

    PubMed  PubMed Central  Google Scholar 

  14. 14

    Kierdorf, K. et al. Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nat. Neurosci. 16, 273–280 (2013). This study demonstrates the nature of microglial precursors and shows molecular and developmental mechanisms for microglial specification.

    CAS  Google Scholar 

  15. 15

    Cunningham, C. L., Martinez-Cerdeno, V. & Noctor, S. C. Microglia regulate the number of neural precursor cells in the developing cerebral cortex. J. Neurosci. 33, 4216–4233 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Ueno, M. et al. Layer V cortical neurons require microglial support for survival during postnatal development. Nat. Neurosci. 16, 543–551 (2013).

    CAS  PubMed  Google Scholar 

  17. 17

    Wakselman, S. et al. Developmental neuronal death in hippocampus requires the microglial CD11b integrin and DAP12 immunoreceptor. J. Neurosci. 28, 8138–8143 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Marin-Teva, J. L. et al. Microglia promote the death of developing Purkinje cells. Neuron 41, 535–547 (2004).

    CAS  PubMed  Google Scholar 

  19. 19

    Frade, J. M. & Barde, Y. A. Microglia-derived nerve growth factor causes cell death in the developing retina. Neuron 20, 35–41 (1998).

    CAS  PubMed  Google Scholar 

  20. 20

    Schafer, D. P. et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74, 691–705 (2012). This article illustrates a surprising role of postnatal microglia in pruning inactive synapses via the classical complement system during development of the visual system.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Stevens, B. et al. The classical complement cascade mediates CNS synapse elimination. Cell 131, 1164–1178 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Paolicelli, R. C. et al. Synaptic pruning by microglia is necessary for normal brain development. Science 333, 1456–1458 (2011). This work shows an unconventional function of microglia in promoting hippocampal synapse maturation and plasticity, possibly through eliminating immature synapses.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Squarzoni, P. et al. Microglia modulate wiring of the embryonic forebrain. Cell Rep. 8, 1271–1279 (2014).

    CAS  PubMed  Google Scholar 

  24. 24

    Pont-Lezica, L. et al. Microglia shape corpus callosum axon tract fasciculation: functional impact of prenatal inflammation. Eur. J. Neurosci. 39, 1551–1557 (2014).

    PubMed  Google Scholar 

  25. 25

    Hoshiko, M., Arnoux, I., Avignone, E., Yamamoto, N. & Audinat, E. Deficiency of the microglial receptor CX3CR1 impairs postnatal functional development of thalamocortical synapses in the barrel cortex. J. Neurosci. 32, 15106–15111 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Ueno, M. & Yamashita, T. Bidirectional tuning of microglia in the developing brain: from neurogenesis to neural circuit formation. Curr. Opin. Neurobiol. 27, 8–15 (2014).

    CAS  PubMed  Google Scholar 

  27. 27

    Ransohoff, R. M. A polarizing question: do M1 and M2 microglia exist? Nat. Neurosci. 19, 987–991 (2016).

    CAS  PubMed  Google Scholar 

  28. 28

    Aguzzi, A., Barres, B. A. & Bennett, M. L. Microglia: scapegoat, saboteur, or something else? Science 339, 156–161 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Prinz, M. & Priller, J. Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nat. Rev. Neurosci. 15, 300–312 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Crotti, A. & Ransohoff, R. M. Microglial physiology and pathophysiology: insights from genome-wide transcriptional profiling. Immunity 44, 505–515 (2016).

    CAS  Google Scholar 

  31. 31

    Colonna, M. & Butovsky, O. Microglia function in the central nervous system during health and neurodegeneration. Annu. Rev. Immunol. 35, 441–468 (2017).

    CAS  PubMed  Google Scholar 

  32. 32

    Wolf, S. A., Boddeke, H. W. & Kettenmann, H. Microglia in physiology and disease. Annu. Rev. Physiol. 79, 619–643 (2017).

    CAS  PubMed  Google Scholar 

  33. 33

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

    CAS  PubMed  Google Scholar 

  34. 34

    Goldmann, T. et al. Origin, fate and dynamics of macrophages at central nervous system interfaces. Nat. Immunol. 17, 797–805 (2016). This work uses fate mapping and parabiosis experiments to demonstrate the ontogeny and dynamics of non-parenchymal macrophages.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    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  Google Scholar 

  36. 36

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

    CAS  Google Scholar 

  37. 37

    Gautier, E. L. et al. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat. Immunol. 13, 1118–1128 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Butovsky, O. et al. Identification of a unique TGF-β-dependent molecular and functional signature in microglia. Nat. Neurosci. 17, 131–143 (2014). This study uses comparative transcriptomic analyses to identify a microglial molecular signature, which further suggests that TGFβ is a brain-specific signal for microglial specification.

    CAS  PubMed  Google Scholar 

  39. 39

    Lavin, Y. et al. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 159, 1312–1326 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Gosselin, D. et al. Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell 159, 1327–1340 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Bennett, M. L. et al. New tools for studying microglia in the mouse and human CNS. Proc. Natl Acad. Sci. USA 113, E1738–E1746 (2016). This work proves that TMEM119 is a microglia-specific marker; antibodies were generated that enable the developmental profiling of highly pure microglia.

    CAS  PubMed  Google Scholar 

  42. 42

    Zhang, Y. et al. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J. Neurosci. 34, 11929–11947 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Grabert, K. et al. Microglial brain region-dependent diversity and selective regional sensitivities to aging. Nat. Neurosci. 19, 504–516 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    De Biase, L. M. et al. Local cues establish and maintain region-specific phenotypes of basal ganglia microglia. Neuron 95, 341–356.e6 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Matcovitch-Natan, O. et al. Microglia development follows a stepwise program to regulate brain homeostasis. Science 353, aad8670 (2016). Using time-course and single-cell RNA-seq analyses, this work shows discrete phases in gene expression during microglial development.

    Google Scholar 

  46. 46

    Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer's disease. Cell 169, 1276–1290.e.17 (2017).

    CAS  Google Scholar 

  47. 47

    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 

  48. 48

    Gomez Perdiguero, E. et al. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 518, 547–551 (2015). This work uses fate mapping and in vitro culture to show that tissue macrophages, including microglia, arise from erythro-myeloid progenitors, which supports Model 2 of microglial and macrophage ontogeny described in this Review.

    PubMed  Google Scholar 

  49. 49

    Hoeffel, G. et al. C-Myb+ erythro-myeloid progenitor-derived fetal monocytes give rise to adult tissue-resident macrophages. Immunity 42, 665–678 (2015). This work demonstrates a major contribution of FL monocytes to adult tissue macrophages, which supports Model 1 of microglial and macrophage ontogeny described in this Review.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Kierdorf, K., Prinz, M., Geissmann, F. & Gomez Perdiguero, E. Development and function of tissue resident macrophages in mice. Semin. Immunol. 27, 369–378 (2015).

    CAS  PubMed  Google Scholar 

  51. 51

    Perdiguero, E. G. & Geissmann, F. The development and maintenance of resident macrophages. Nat. Immunol. 17, 2–8 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Palis, J. Hematopoietic stem cell-independent hematopoiesis: emergence of erythroid, megakaryocyte, and myeloid potential in the mammalian embryo. FEBS Lett. 590, 3965–3974 (2016).

    CAS  PubMed  Google Scholar 

  53. 53

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Askew, K. et al. Coupled proliferation and apoptosis maintain the rapid turnover of microglia in the adult brain. Cell Rep. 18, 391–405 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    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).

    CAS  PubMed  Google Scholar 

  56. 56

    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  PubMed Central  Google Scholar 

  57. 57

    Guilliams, M. & Scott, C. L. Does niche competition determine the origin of tissue-resident macrophages? Nat. Rev. Immunol. 17, 451–460 (2017).

    CAS  PubMed  Google Scholar 

  58. 58

    van de Laar, L. et al. Yolk sac macrophages, fetal liver, and adult monocytes can colonize an empty niche and develop into functional tissue-resident macrophages. Immunity 44, 755–768 (2016).

    CAS  PubMed  Google Scholar 

  59. 59

    Jin, H. et al. Runx1 regulates embryonic myeloid fate choice in zebrafish through a negative feedback loop inhibiting Pu.1 expression. Blood 119, 5239–5249 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Xu, J., Wang, T., Wu, Y., Jin, W. & Wen, Z. Microglia colonization of developing zebrafish midbrain is promoted by apoptotic neuron and lysophosphatidylcholine. Dev. Cell 38, 214–222 (2016).

    CAS  PubMed  Google Scholar 

  61. 61

    Casano, A. M., Albert, M. & Peri, F. Developmental apoptosis mediates entry and positioning of microglia in the zebrafish brain. Cell Rep. 16, 897–906 (2016).

    CAS  PubMed  Google Scholar 

  62. 62

    Swinnen, N. et al. Complex invasion pattern of the cerebral cortex bymicroglial cells during development of the mouse embryo. Glia 61, 150–163 (2013).

    PubMed  Google Scholar 

  63. 63

    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).

    CAS  PubMed  Google Scholar 

  64. 64

    Lawson, L. J., Perry, V. H. & Gordon, S. Turnover of resident microglia in the normal adult mouse brain. Neuroscience 48, 405–415 (1992).

    CAS  PubMed  Google Scholar 

  65. 65

    Fuger, 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 

  66. 66

    Ueno, H. & Weissman, I. L. Clonal analysis of mouse development reveals a polyclonal origin for yolk sac blood islands. Dev. Cell 11, 519–533 (2006).

    CAS  PubMed  Google Scholar 

  67. 67

    Chitu, V., Gokhan, S., Nandi, S., Mehler, M. F. & Stanley, E. R. Emerging roles for CSF-1 receptor and its ligands in the nervous system. Trends Neurosci. 39, 378–393 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Chitu, V. & Stanley, E. R. Regulation of embryonic and postnatal development by the CSF-1 receptor. Curr. Top. Dev. Biol. 123, 229–275 (2017).

    PubMed  Google Scholar 

  69. 69

    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 

  70. 70

    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 

  71. 71

    Abud, E. M. et al. iPSC-derived human microglia-like cells to study neurological diseases. Neuron 94, 278–293.e9 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Douvaras, P. et al. Directed differentiation of human pluripotent stem cells to microglia. Stem Cell Rep. 8, 1516–1524 (2017).

    CAS  Google Scholar 

  73. 73

    Haenseler, W. et al. A highly efficient human pluripotent stem cell microglia model displays a neuronal-co-culture-specific expression profile and inflammatory response. Stem Cell Rep. 8, 1727–1742 (2017).

    CAS  Google Scholar 

  74. 74

    Mossadegh-Keller, N. et al. M-CSF instructs myeloid lineage fate in single haematopoietic stem cells. Nature 497, 239–243 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Rosenbauer, F. et al. Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1. Nat. Genet. 36, 624–630 (2004).

    CAS  PubMed  Google Scholar 

  76. 76

    Elmore, M. R. et al. Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron 82, 380–397 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Buttgereit, A. et al. Sall1 is a transcriptional regulator defining microglia identity and function. Nat. Immunol. 17, 1397–1406 (2016).

    CAS  PubMed  Google Scholar 

  78. 78

    Bohlen, C. J. et al. Diverse requirements for microglial survival, specification, and function revealed by defined-medium cultures. Neuron 94, 759–773.e8 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Wang, Y. et al. IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia. Nat. Immunol. 13, 753–760 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Greter, M. et al. Stroma-derived interleukin-34 controls the development and maintenance of langerhans cells and the maintenance of microglia. Immunity 37, 1050–1060 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Nandi, S. et al. The CSF-1 receptor ligands IL-34 and CSF-1 exhibit distinct developmental brain expression patterns and regulate neural progenitor cell maintenance and maturation. Dev. Biol. 367, 100–113 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Mass, E. et al. Specification of tissue-resident macrophages during organogenesis. Science 353, aaf4238 (2016).

    PubMed  PubMed Central  Google Scholar 

  83. 83

    Abutbul, S. et al. TGF-β signaling through SMAD2/3 induces the quiescent microglial phenotype within the CNS environment. Glia 60, 1160–1171 (2012).

    PubMed  Google Scholar 

  84. 84

    Gosselin, D. et al. An environment-dependent transcriptional network specifies human microglia identity. Science 356, eaal3222 (2017).

    PubMed  PubMed Central  Google Scholar 

  85. 85

    Cohen, M. et al. Chronic exposure to TGFβ1 regulates myeloid cell inflammatory response in an IRF7-dependent manner. EMBO J. 33, 2906–2921 (2014).

    PubMed  PubMed Central  Google Scholar 

  86. 86

    Endo, F. et al. Astrocyte-derived TGF-β1 accelerates disease progression in ALS mice by interfering with the neuroprotective functions of microglia and T cells. Cell Rep. 11, 592–604 (2015).

    CAS  PubMed  Google Scholar 

  87. 87

    Wong, K. et al. Mice deficient in NRROS show abnormal microglial development and neurological disorders. Nat. Immunol. 18, 633–641 (2017).

    CAS  PubMed  Google Scholar 

  88. 88

    Amit, I., Winter, D. R. & Jung, S. The role of the local environment and epigenetics in shaping macrophage identity and their effect on tissue homeostasis. Nat. Immunol. 17, 18–25 (2016).

    CAS  PubMed  Google Scholar 

  89. 89

    Li, Y., Du, X. F., Liu, C. S., Wen, Z. L. & Du, J. L. Reciprocal regulation between resting microglial dynamics and neuronal activity in vivo. Dev. Cell 23, 1189–1202 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Dissing-Olesen, L. et al. Activation of neuronal NMDA receptors triggers transient ATP-mediated microglial process outgrowth. J. Neurosci. 34, 10511–10527 (2014).

    PubMed  Google Scholar 

  91. 91

    Zhan, Y. et al. Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior. Nat. Neurosci. 17, 400–406 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

    Sipe, G. O. et al. Microglial P2Y12 is necessary for synaptic plasticity in mouse visual cortex. Nat. Commun. 7, 10905 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Stephan, A. H., Barres, B. A. & Stevens, B. The complement system: an unexpected role in synaptic pruning during development and disease. Annu. Rev. Neurosci. 35, 369–389 (2012).

    CAS  PubMed  Google Scholar 

  94. 94

    Chu, Y. et al. Enhanced synaptic connectivity and epilepsy in C1q knockout mice. Proc. Natl Acad. Sci. USA 107, 7975–7980 (2010).

    CAS  PubMed  Google Scholar 

  95. 95

    Hong, S. et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352, 712–716 (2016). This study shows that developmental functions of microglia can be erroneously re-activated and that this underlies synapse loss in a neurodegenerative disease.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Lui, H. et al. Progranulin deficiency promotes circuit-specific synaptic pruning by microglia via complement activation. Cell 165, 921–935 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Vasek, M. J. et al. A complement-microglial axis drives synapse loss during virus-induced memory impairment. Nature 534, 538–543 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98

    Shi, Q. et al. Complement C3-deficient mice fail to display age-related hippocampal decline. J. Neurosci. 35, 13029–13042 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Sekar, A. et al. Schizophrenia risk from complex variation of complement component 4. Nature 530, 177–183 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    Stephan, A. H. et al. A dramatic increase of C1q protein in the CNS during normal aging. J. Neurosci. 33, 13460–13474 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    Chung, W. S. et al. Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways. Nature 504, 394–400 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102

    Sierra, A. et al. Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell 7, 483–495 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103

    Fourgeaud, L. et al. TAM receptors regulate multiple features of microglial physiology. Nature 532, 240–244 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104

    Chiu, I. M. et al. A neurodegeneration-specific gene-expression signature of acutely isolated microglia from an amyotrophic lateral sclerosis mouse model. Cell Rep. 4, 385–401 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105

    Yin, Z. et al. Immune hyperreactivity of Abeta plaque-associated microglia in Alzheimer's disease. Neurobiol. Aging 55, 115–122 (2017).

    CAS  PubMed  Google Scholar 

  106. 106

    Tsuda, M. P2 receptors, microglial cytokines and chemokines, and neuropathic pain. J. Neurosci. Res. 95, 1319–1329 (2017).

    CAS  PubMed  Google Scholar 

  107. 107

    Guan, Z. et al. Injured sensory neuron-derived CSF1 induces microglial proliferation and DAP12-dependent pain. Nat. Neurosci. 19, 94–101 (2016).

    CAS  PubMed  Google Scholar 

  108. 108

    Coull, J. A. et al. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438, 1017–1021 (2005).

    CAS  PubMed  Google Scholar 

  109. 109

    Zhuang, Z. Y. et al. Role of the CX3CR1/p38 MAPK pathway in spinal microglia for the development of neuropathic pain following nerve injury-induced cleavage of fractalkine. Brain Behav. Immun. 21, 642–651 (2007).

    CAS  PubMed  Google Scholar 

  110. 110

    Davalos, D. et al. ATP mediates rapid microglial response to local brain injury in vivo. Nat. Neurosci. 8, 752–758 (2005).

    CAS  PubMed  Google Scholar 

  111. 111

    Haynes, S. E. et al. The P2Y12 receptor regulates microglial activation by extracellular nucleotides. Nat. Neurosci. 9, 1512–1519 (2006).

    CAS  PubMed  Google Scholar 

  112. 112

    Roth, T. L. et al. Transcranial amelioration of inflammation and cell death after brain injury. Nature 505, 223–228 (2014).

    CAS  PubMed  Google Scholar 

  113. 113

    Lou, N. et al. Purinergic receptor P2RY12-dependent microglial closure of the injured blood-brain barrier. Proc. Natl Acad. Sci. USA 113, 1074–1079 (2016).

    CAS  PubMed  Google Scholar 

  114. 114

    Orr, A. G., Orr, A. L., Li, X. J., Gross, R. E. & Traynelis, S. F. Adenosine A2A receptor mediates microglial process retraction. Nat. Neurosci. 12, 872–878 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115

    Liddelow, S. A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116

    Hagemeyer, N. et al. Microglia contribute to normal myelinogenesis and to oligodendrocyte progenitor maintenance during adulthood. Acta Neuropathol. 134, 441–458 (2017).

    PubMed  PubMed Central  Google Scholar 

  117. 117

    Miron, V. E. et al. M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat. Neurosci. 16, 1211–1218 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118

    Safaiyan, S. et al. Age-related myelin degradation burdens the clearance function of microglia during aging. Nat. Neurosci. 19, 995–998 (2016).

    CAS  PubMed  Google Scholar 

  119. 119

    Fantin, A. et al. Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction. Blood 116, 829–840 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120

    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 

  121. 121

    Zusso, M. et al. Regulation of postnatal forebrain amoeboid microglial cell proliferation and development by the transcription factor Runx1. J. Neurosci. 32, 11285–11298 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122

    Shigemoto-Mogami, Y., Hoshikawa, K., Goldman, J. E., Sekino, Y. & Sato, K. Microglia enhance neurogenesis and oligodendrogenesis in the early postnatal subventricular zone. J. Neurosci. 34, 2231–2243 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123

    Ransohoff, R. M. How neuroinflammation contributes to neurodegeneration. Science 353, 777–783 (2016).

    CAS  PubMed  Google Scholar 

  124. 124

    Ajami, B., Bennett, J. L., Krieger, C., McNagny, K. M. & Rossi, F. M. Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nat. Neurosci. 14, 1142–1149 (2011).

    CAS  PubMed  Google Scholar 

  125. 125

    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 

  126. 126

    Ritzel, R. M. et al. Functional differences between microglia and monocytes after ischemic stroke. J. Neuroinflamm. 12, 106 (2015).

    Google Scholar 

  127. 127

    Guerreiro, R. et al. TREM2 variants in Alzheimer's disease. N. Engl. J. Med. 368, 117–127 (2013).

    CAS  PubMed  Google Scholar 

  128. 128

    Sims, R. et al. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. Nat. Genet. 49, 1373–1384 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 129

    Jonsson, T. et al. Variant of TREM2 associated with the risk of Alzheimer's disease. N. Engl. J. Med. 368, 107–116 (2013).

    CAS  PubMed  Google Scholar 

  130. 130

    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).

    CAS  PubMed  Google Scholar 

  131. 131

    Hollingworth, P. et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nat. Genet. 43, 429–435 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132

    Naj, A. C. et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nat. Genet. 43, 436–441 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133

    Carrasquillo, M. M. et al. Replication of EPHA1 and CD33 associations with late-onset Alzheimer's disease: a multi-centre case-control study. Mol. Neurodegener. 6, 54 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134

    Colonna, M. & Wang, Y. TREM2 variants: new keys to decipher Alzheimer disease pathogenesis. Nat. Rev. Neurosci. 17, 201–207 (2016).

    CAS  PubMed  Google Scholar 

  135. 135

    Griciuc, A. et al. Alzheimer's disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron 78, 631–643 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136

    Grathwohl, S. A. et al. Formation and maintenance of Alzheimer's disease β-amyloid plaques in the absence of microglia. Nat. Neurosci. 12, 1361–1363 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137

    Yuan, P. et al. TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy. Neuron 90, 724–739 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138

    Asai, H. et al. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat. Neurosci. 18, 1584–1593 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139

    Yoshiyama, Y. et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53, 337–351 (2007).

    CAS  PubMed  Google Scholar 

  140. 140

    Maphis, N. et al. Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain. Brain 138, 1738–1755 (2015).

    PubMed  PubMed Central  Google Scholar 

  141. 141

    Al-Chalabi, A., van den Berg, L. H. & Veldink, J. Gene discovery in amyotrophic lateral sclerosis: implications for clinical management. Nat. Rev. Neurol. 13, 96–104 (2017).

    CAS  PubMed  Google Scholar 

  142. 142

    Boillee, S. et al. Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312, 1389–1392 (2006).

    CAS  PubMed  Google Scholar 

  143. 143

    O'Rourke, J. G. et al. C9orf72 is required for proper macrophage and microglial function in mice. Science 351, 1324–1329 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144

    Paolicelli, R. C. et al. TDP-43 depletion in microglia promotes amyloid clearance but also induces synapse loss. Neuron 95, 297–308 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145

    Mishra, M. K. & Yong, V. W. Myeloid cells — targets of medication in multiple sclerosis. Nat. Rev. Neurol. 12, 539–551 (2016).

    CAS  PubMed  Google Scholar 

  146. 146

    International Multiple Sclerosis Genetics, C. et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476, 214–219 (2011).

  147. 147

    Miron, V. E. Microglia-driven regulation of oligodendrocyte lineage cells, myelination, and remyelination. J. Leukoc. Biol. 101, 1103–1108 (2017).

    CAS  PubMed  Google Scholar 

  148. 148

    Beutner, C., Roy, K., Linnartz, B., Napoli, I. & Neumann, H. Generation of microglial cells from mouse embryonic stem cells. Nat. Protoc. 5, 1481–1494 (2010).

    CAS  PubMed  Google Scholar 

  149. 149

    Tavian, M. & Peault, B. Embryonic development of the human hematopoietic system. Int. J. Dev. Biol. 49, 243–250 (2005).

    CAS  PubMed  Google Scholar 

  150. 150

    Monier, A. et al. Entry and distribution of microglial cells in human embryonic and fetal cerebral cortex. J. Neuropathol. Exp. Neurol. 66, 372–382 (2007).

    PubMed  Google Scholar 

  151. 151

    Karch, C. M. & Goate, A. M. Alzheimer's disease risk genes and mechanisms of disease pathogenesis. Biol Psychiatry 77, 43–51 (2015).

    CAS  PubMed  Google Scholar 

  152. 152

    Wang, Y. et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model. Cell 160, 1061–1071 (2015). This work demonstrates lipid sensing by TREM2, which is encoded by one of the strongest risk genes for Alzheimer disease, as a possible mechanism underlying disease pathophysiology.

    CAS  PubMed  PubMed Central  Google Scholar 

  153. 153

    Yeh, F. L., Wang, Y., Tom, I., Gonzalez, L. C. & Sheng, M. TREM2 Binds to apolipoproteins, including APOE and CLU/APOJ, and thereby facilitates uptake of amyloid-β by microglia. Neuron 91, 328–340 (2016).

    CAS  PubMed  Google Scholar 

  154. 154

    Wang, Y. et al. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J. Exp. Med. 213, 667–675 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. 155

    Ulland, T. K. et al. TREM2 maintains microglial metabolic fitness in Alzheimer's disease. Cell 170, 649–663.e13 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. 156

    Dai, X. M. et al. Targeted disruption of the mouse colony-stimulating factor 1 receptor gene results in osteopetrosis, mononuclear phagocyte deficiency, increased primitive progenitor cell frequencies, and reproductive defects. Blood 99, 111–120 (2002).

    CAS  PubMed  Google Scholar 

  157. 157

    Otero, K. et al. Macrophage colony-stimulating factor induces the proliferation and survival of macrophages via a pathway involving DAP12 and β-catenin. Nat. Immunol. 10, 734–743 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references


The authors thank members of the Barres laboratory for providing valuable feedback, especially C. J. Bohlen, M.-M. Fu, F. C. Bennett, M. L. Bennett and L. Zhou. Q.L. is supported by the Jeffry M. and Barbara Picower (JPB) foundation and Stanford University School of Medicine Dean's Postdoctoral Fellowship.

Author information




Q.L. was responsible for researching, writing and editing the manuscript. B.A.B. contributed to reviewing and editing the manuscript before submission.

Corresponding authors

Correspondence to Qingyun Li or Ben A. Barres.

Ethics declarations

Competing interests

B.A.B. is a co-founder of Annexon Biosciences, Inc., a company that is making drugs for neurological diseases. Q.L. declares no conflict of interest.

PowerPoint slides


Blood–brain barrier

(BBB). A physiological barrier between blood vessels and brain parenchyma. It is formed by specialized tight junctions between endothelial cells of the blood vessel wall, which is surrounded by a basement membrane and an additional membrane formed from astrocytic end feet, known as the glial basement membrane (glia limitans).

Basal ganglia

A group of interconnected nuclei (clusters of neurons) that lie deep beneath the cerebral cortex. They are responsible for modulating motor control, planning actions and executing habitual behaviours, as well as influencing cognition and emotion.


An experimental model system in which two animals (most often mice) are surgically joined to establish a common circulation.

Epigenetic memory

Molecular mechanisms modifying DNA or chromosomal configuration without changing gene sequences that lead to stable changes in gene expression long after the disappearance of initial developmental or environmental signals.

Complement system

A signalling cascade that can be activated by any of three independent pathways. The classical pathway is activated by antigen–antibody immune complexes. The alternative pathway is triggered by direct hydrolysis of complement component C3. The lectin pathway is activated by the binding of lectin to mannose residues on the surface of pathogens.

Layer V neurons

Neurons in layer V of the six-layered mammalian neocortex. This layer contains excitatory neurons that project either to the contralateral hemisphere or to subcortical brain regions, such as the thalamus and brainstem.

Axon fasciculation

A neurodevelopmental process in which axons that travel in the same direction often adhere together to form a tight bundle.

Corpus callosum

A thick bundle of nerve fibres that connect the left and right hemispheres of the brain and form the most prominent white-matter structure.


A member of a class of neurodegenerative disorders that are manifested by intracellular accumulation of hyperphosphorylated microtubule-associated protein tau. These insoluble protein aggregates form neurofibrillary tangles and often underlie the pathological conditions of dementia and Parkinson disease.

Nodes of Ranvier

Periodic axonal segments, rich in ion channels, that are not covered by myelin sheaths; this allows rapid propagation of an action potential from one node of Ranvier to the next along the fibre.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Li, Q., Barres, B. Microglia and macrophages in brain homeostasis and disease. Nat Rev Immunol 18, 225–242 (2018). https://doi.org/10.1038/nri.2017.125

Download citation

Further reading


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