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.

  • Review Article
  • Published:

Microglial signatures and their role in health and disease

Nature Reviews Neuroscience volume 19, pages 622–635 (2018)Cite this article

Subjects

Abstract

Microglia are the primary innate immune cells in the CNS. In the healthy brain, they exhibit a unique molecular homeostatic ‘signature’, consisting of a specific transcriptional profile and surface protein expression pattern, which differs from that of tissue macrophages. In recent years, there have been a number of important advances in our understanding of the molecular signatures of homeostatic microglia and disease-associated microglia that have provided insight into how these cells are regulated in health and disease and how they contribute to the maintenance of the neural environment.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Regulation of microglia homeostasis.
Fig. 2: Regulation of the neurodegenerative microglial phenotype.

Similar content being viewed by others

References

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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. Li, Q. & Barres, B. A. Microglia and macrophages in brain homeostasis and disease. Nat. Rev. Immunol. (2017).

  4. Sarlus, H. & Heneka, M. T. Microglia in Alzheimer’s disease. J. Clin. Invest. 127, 3240–3249 (2017).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  6. Kaur, C., Hao, A. J., Wu, C. H. & Ling, E. A. Origin of microglia. Microsc. Res. Tech. 54, 2–9 (2001).

    CAS  PubMed  Google Scholar 

  7. 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).

    CAS  PubMed  Google Scholar 

  8. Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010).References 7 and 8 identify microglia as originating from yolk-sac-derived primitive macrophages.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. van Furth, R. & Cohn, Z. A. The origin and kinetics of mononuclear phagocytes. J. Exp. Med. 128, 415–435 (1968).

    PubMed  PubMed Central  Google Scholar 

  10. Kierdorf, K. et al. Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nat. Neurosci. 16, 273–280 (2013).This study shows that microglia derived from erythromyeloid precursors develop into CD45 + c-kit lo CX 3 CR1 – immature (A1) cells and mature into CD45 + c-kit – CX 3 CR1 + (A2) cells. Both PU.1 and IRF8 transcription factors are vital for the development of A2 microglia.

    CAS  PubMed  Google Scholar 

  11. Neumann, H. & Wekerle, H. Brain microglia: watchdogs with pedigree. Nat. Neurosci. 16, 253–255 (2013).

    CAS  PubMed  Google Scholar 

  12. Bruttger, J. et al. Genetic cell ablation reveals clusters of local self-renewing microglia in the mammalian central nervous system. Immunity 43, 92–106 (2015). This study reports that microglia have the potential to self-renew without the need for a contribution of peripheral myeloid cells.

    CAS  PubMed  Google Scholar 

  13. 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 

  14. Askew, K. et al. Coupled proliferation and apoptosis maintain the rapid turnover of microglia in the adult brain. Cell Rep. 18, 391–405 (2017).References 13 and 14 show that microglia self-renew stochastically in the healthy brain and expand clonally during disease. The resulting excess in microglia is resolved by cell egress and programmed cell death.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Reu, P. et al. The lifespan and turnover of microglia in the human brain. Cell Rep. 20, 779–784 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Huang, Y. et al. Repopulated microglia are solely derived from the proliferation of residual microglia after acute depletion. Nat. Neurosci. 21, 530–540 (2018).

    CAS  PubMed  Google Scholar 

  17. Cronk, J. C. et al. Peripherally derived macrophages can engraft the brain independent of irradiation and maintain an identity distinct from microglia. J. Exp. Med. https://doi.org/10.1084/jem.20180247 (2018).This study shows that microglial populations can be replaced with peripherally derived macrophages that maintain a unique identity and distinct functional role in the CNS compared with microglia.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Lund, H. et al. Fatal demyelinating disease is induced by monocyte-derived macrophages in the absence of TGF-beta signaling. Nat. Immunol. 19, 1–7 (2018).This study demonstrates that peripherally derived macrophages engraft the brain after microglia depletion and that TGFβ plays a critical role in preventing microglia-and/or macrophage-mediated CNS pathology.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Ransohoff, R. M. & Cardona, A. E. The myeloid cells of the central nervous system parenchyma. Nature 468, 253–262 (2010).

    CAS  PubMed  Google Scholar 

  20. Kettenmann, H., Hanisch, U. K., Noda, M. & Verkhratsky, A. Physiology of microglia. Physiol. Rev. 91, 461–553 (2011).

    CAS  PubMed  Google Scholar 

  21. Hanisch, U. K. & Kettenmann, H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat. Neurosci. 10, 1387–1394 (2007).

    CAS  PubMed  Google Scholar 

  22. Hanisch, U. K. Functional diversity of microglia - how heterogeneous are they to begin with? Front. Cell. Neurosci. 7, 65 (2013).

    PubMed  PubMed Central  Google Scholar 

  23. Mantovani, A., Sica, A. & Locati, M. Macrophage polarization comes of age. Immunity 23, 344–346 (2005).

    CAS  PubMed  Google Scholar 

  24. Martinez, F. O. & Gordon, S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 6, 13 (2014).This review discusses the limitations of using the M1 and M2 paradigm, which does not represent the broader functional repertoire of macrophage biology.

    PubMed  PubMed Central  Google Scholar 

  25. Butovsky, O. et al. Identification of a unique TGF-beta-dependent molecular and functional signature in microglia. Nat. Neurosci. 17, 131–143 (2014).This study identifies the molecular and functional signature of homeostatic microglia, which depends on TGFβ signalling.

    CAS  PubMed  Google Scholar 

  26. Holtman, I. R. et al. Induction of a common microglia gene expression signature by aging and neurodegenerative conditions: a co-expression meta-analysis. Acta Neuropathol. Commun. 3, 31 (2015).

    PubMed  PubMed Central  Google Scholar 

  27. Hickman, S. E. et al. The microglial sensome revealed by direct RNA sequencing. Nat. Neurosci. 16, 1896–1905 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 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 

  29. 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 

  30. Gosselin, D. et al. An environment-dependent transcriptional network specifies human microglia identity. Science. https://doi.org/10.1126/science.aal3222 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Galatro, T. F. et al. Transcriptomic analysis of purified human cortical microglia reveals age-associated changes. Nat. Neurosci. 20, 1162–1171 (2017).

    CAS  PubMed  Google Scholar 

  32. Olah, M. et al. A transcriptomic atlas of aged human microglia. Nat. Commun. 9, 539 (2018).

    PubMed  PubMed Central  Google Scholar 

  33. Satoh, J. et al. TMEM119 marks a subset of microglia in the human brain. Neuropathology 36, 39–49 (2016).

    CAS  PubMed  Google Scholar 

  34. Zhu, C. et al. Expression site of P2RY12 in residential microglial cells in astrocytomas correlates with M1 and M2 marker expression and tumor grade. Acta Neuropathol. Commun. 5, 4 (2017).

    PubMed  PubMed Central  Google Scholar 

  35. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Zrzavy, T. et al. Loss of ‘homeostatic’ microglia and patterns of their activation in active multiple sclerosis. Brain 140, 1900–1913 (2017).

    PubMed  PubMed Central  Google Scholar 

  37. 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 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  41. Perry, V. H., Hume, D. A. & Gordon, S. Immunohistochemical localization of macrophages and microglia in the adult and developing mouse brain. Neuroscience 15, 313–326 (1985).

    CAS  PubMed  Google Scholar 

  42. Akiyama, H. & McGeer, P. L. Brain microglia constitutively express beta-2 integrins. J. Neuroimmunol. 30, 81–93 (1990).

    CAS  PubMed  Google Scholar 

  43. Ginhoux, F. & Prinz, M. Origin of microglia: current concepts and past controversies. Cold Spring Harb. Perspect. Biol. 7, a020537 (2015).

    PubMed  PubMed Central  Google Scholar 

  44. Vainchtein, I. D. et al. In acute experimental autoimmune encephalomyelitis, infiltrating macrophages are immune activated, whereas microglia remain immune suppressed. Glia 62, 1724–1735 (2014).

    CAS  PubMed  Google Scholar 

  45. van den Berg, T. K., Puklavec, M. J., Barclay, A. N. & Dijkstra, C. D. Monoclonal antibodies against rat leukocyte surface antigens. Immunol. Rev. 184, 109–116 (2001).

    PubMed  Google Scholar 

  46. 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 

  47. Sousa, C., Biber, K. & Michelucci, A. Cellular and molecular characterization of microglia: a unique immune cell population. Front. Immunol. 8, 198 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Davies, L. C., Jenkins, S. J., Allen, J. E. & Taylor, P. R. Tissue-resident macrophages. Nat. Immunol. 14, 986–995 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Butovsky, O. et al. Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS. J. Clin. Invest. 122, 3063–3087 (2012).This study shows the relevance of innate inflammation for ALS pathogenesis and identifies miR-155 as a potential therapeutic target.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Gao, L. et al. Infiltration of circulating myeloid cells through CD95L contributes to neurodegeneration in mice. J. Exp. Med. 212, 469–480 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Zondler, L. et al. Peripheral monocytes are functionally altered and invade the CNS in ALS patients. Acta Neuropathol. 132, 391–411 (2016).

    CAS  PubMed  Google Scholar 

  52. Krasemann, S. et al. The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47, 566–581 (2017).This study identifies a major microglial neurodegenerative phenotype in rodent and humans regulated by TREM2–ApoE signalling.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  54. Konishi, H. et al. Siglec-H is a microglia-specific marker that discriminates microglia from CNS-associated macrophages and CNS-infiltrating monocytes. Glia 65, 1927–1943 (2017).

    PubMed  Google Scholar 

  55. Lawson, L. J., Perry, V. H., Dri, P. & Gordon, S. Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience 39, 151–170 (1990).

    CAS  PubMed  Google Scholar 

  56. Hua, K., Schindler, M. K., McQuail, J. A., Forbes, M. E. & Riddle, D. R. Regionally distinct responses of microglia and glial progenitor cells to whole brain irradiation in adult and aging rats. PLOS ONE 7, e52728 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Schmid, C. D. et al. Heterogeneous expression of the triggering receptor expressed on myeloid cells-2 on adult murine microglia. J. Neurochem. 83, 1309–1320 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  59. Grabert, K. et al. Microglial brain region-dependent diversity and selective regional sensitivities to aging. Nat. Neurosci. 19, 504–516 (2016).This study describes the age-dependent and region-dependent transcriptional heterogeneity of microglia.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Raj, D. et al. Increased white matter inflammation in aging- and alzheimer’s disease brain. Front. Mol. Neurosci. 10, 206 (2017).

    PubMed  PubMed Central  Google Scholar 

  61. 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).

    CAS  PubMed  Google Scholar 

  62. Ladeby, R. et al. Microglial cell population dynamics in the injured adult central nervous system. Brain Res. Rev. 48, 196–206 (2005).

    CAS  PubMed  Google Scholar 

  63. Ziebell, J. M., Adelson, P. D. & Lifshitz, J. Microglia: dismantling and rebuilding circuits after acute neurological injury. Metab. Brain Dis. 30, 393–400 (2015).

    PubMed  Google Scholar 

  64. Tremblay, M. È. et al. The role of microglia in the healthy brain. J. Neurosci. 31, 16064–16069 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Gomez-Nicola, D. & Perry, V. H. Microglial dynamics and role in the healthy and diseased brain: a paradigm of functional plasticity. Neuroscientist 21, 169–184 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Michell-Robinson, M. A. et al. Roles of microglia in brain development, tissue maintenance and repair. Brain 138, 1138–1159 (2015).

    PubMed  PubMed Central  Google Scholar 

  67. 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 

  68. 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 

  69. Madry, C. et al. Microglial ramification, surveillance, and interleukin-1ß release are regulated by the two-pore domain K(+) channel THIK-1. Neuron 97, 299–312 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Friedman, A. D. Transcriptional control of granulocyte and monocyte development. Oncogene 26, 6816–6828 (2007).

    CAS  PubMed  Google Scholar 

  71. Anderson, K. L. et al. Myeloid development is selectively disrupted in PU.1 null mice. Blood 91, 3702–3710 (1998).This study demonstrates that PU.1 gene disruption affects a number of developmentally regulated haematopoietic processes and myeloid development.

    CAS  PubMed  Google Scholar 

  72. Herbomel, P., Thisse, B. & Thisse, C. Zebrafish early macrophages colonize cephalic mesenchyme and developing brain, retina, and epidermis through a M-CSF receptor-dependent invasive process. Dev. Biol. 238, 274–288 (2001).

    CAS  PubMed  Google Scholar 

  73. Satoh, J., Asahina, N., Kitano, S. & Kino, Y. A. Comprehensive profile of ChIP-Seq-based PU.1/Spi1 target genes in microglia. Gene Regul. Syst. Bio. 8, 127–139 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Heinz, S. et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol. Cell 38, 576–589 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 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 

  76. Lavin, Y. et al. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 159, 1312–1326 (2014).References 75 and 76 provide evidence that the tissue environment is a major determinant of resident macrophage gene expression and that PU.1 binds SMAD3 to establish a microglial-specific enhancer profile.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Deczkowska, A. et al. Mef2C restrains microglial inflammatory response and is lost in brain ageing in an IFN-I-dependent manner. Nat. Commun. 8, 717 (2017).

    PubMed  PubMed Central  Google Scholar 

  78. Cardona, A. E. et al. Control of microglial neurotoxicity by the fractalkine receptor. Nat. Neurosci. 9, 917–924 (2006).

    CAS  PubMed  Google Scholar 

  79. Limatola, C. & Ransohoff, R. M. Modulating neurotoxicity through CX3CL1/CX3CR1 signaling. Front. Cell. Neurosci. 8, 229 (2014).

    PubMed  PubMed Central  Google Scholar 

  80. Cuevas, V. D. et al. MAFB determines human macrophage anti-inflammatory polarization: relevance for the pathogenic mechanisms operating in multicentric carpotarsal osteolysis. J. Immunol. 198, 2070–2081 (2017).

    CAS  PubMed  Google Scholar 

  81. Soucie, E. L. et al. Lineage-specific enhancers activate self-renewal genes in macrophages and embryonic stem cells. Science 351, aad5510 (2016).

    PubMed  PubMed Central  Google Scholar 

  82. Matcovitch-Natan, O. et al. Microglia development follows a stepwise program to regulate brain homeostasis. Science 353, aad8670 (2016).This study uses single-cell RNA-sequencing and bioinformatics to describe microglial transcriptome profiles and temporal stages of development in early, pre-adult microglia, which are regulated by distinct regulatory circuits.

    PubMed  Google Scholar 

  83. Koshida, R., Oishi, H., Hamada, M. & Takahashi, S. MafB antagonizes phenotypic alteration induced by GM-CSF in microglia. Biochem. Biophys. Res. Commun. 463, 109–115 (2015).

    CAS  PubMed  Google Scholar 

  84. Butovsky, O. et al. Targeting miR-155 restores abnormal microglia and attenuates disease in SOD1 mice. Ann. Neurol. 77, 75–99 (2015).This study validates miR-155 as a therapeutic target to modulate microglia in a mouse model and in human ALS.

    CAS  PubMed  Google Scholar 

  85. Harrison, S. J., Nishinakamura, R., Jones, K. R. & Monaghan, A. P. Sall1 regulates cortical neurogenesis and laminar fate specification in mice: implications for neural abnormalities in Townes-Brocks syndrome. Dis. Model. Mech. 5, 351–365 (2012).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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. Bialas, A. R. & Stevens, B. TGF-beta signaling regulates neuronal C1q expression and developmental synaptic refinement. Nat. Neurosci. 16, 1773–1782 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Schafer, D. P. & Stevens, B. Phagocytic glial cells: sculpting synaptic circuits in the developing nervous system. Curr. Opin. Neurobiol. 23, 1034–1040 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Paolicelli, R. C. et al. Synaptic pruning by microglia is necessary for normal brain development. Science 333, 1456–1458 (2011).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  92. Hong, S. et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352, 712–716 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Shi, Q. et al. Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice. Sci. Transl Med. https://doi.org/10.1126/scitranslmed.aaf6295 (2017).References 91–93 provide evidence for the role of complement in synaptic elimination by microglia.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Shi, S. H., Jan, L. Y. & Jan, Y. N. Hippocampal neuronal polarity specified by spatially localized mPar3/mPar6 and PI 3-kinase activity. Cell 112, 63–75 (2003).

    CAS  PubMed  Google Scholar 

  95. Kettenmann, H., Kirchhoff, F. & Verkhratsky, A. Microglia: new roles for the synaptic stripper. Neuron 77, 10–18 (2013).

    CAS  PubMed  Google Scholar 

  96. Parkhurst, C. N. et al. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155, 1596–1609 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Zhang, J. et al. Neurotrophins regulate proliferation and survival of two microglial cell lines in vitro. Exp. Neurol. 183, 469–481 (2003).

    CAS  PubMed  Google Scholar 

  98. Elkabes, S., DiCicco-Bloom, E. M. & Black, I. B. Brain microglia/macrophages express neurotrophins that selectively regulate microglial proliferation and function. J. Neurosci. 16, 2508–2521 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Batchelor, P. E. et al. Activated macrophages and microglia induce dopaminergic sprouting in the injured striatum and express brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor. J. Neurosci. 19, 1708–1716 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 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 

  101. Tong, L. et al. Brain-derived neurotrophic factor-dependent synaptic plasticity is suppressed by interleukin-1beta via p38 mitogen-activated protein kinase. J. Neurosci. 32, 17714–17724 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 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).Using a parabiosis paradigm, this study shows that recruited monocytes do not contribute to the resident microglial pool.

    CAS  PubMed  Google Scholar 

  103. 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 

  104. Varvel, N. H. et al. Infiltrating monocytes promote brain inflammation and exacerbate neuronal damage after status epilepticus. Proc. Natl Acad. Sci. USA 113, E5665–E5674 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 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 

  106. Fourgeaud, L. et al. TAM receptors regulate multiple features of microglial physiology. Nature 532, 240–244 (2016).This study shows that microglial MERTK is essential for elimination of apoptotic cells in neurogenic regions of the CNS.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Ziv, Y. et al. Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat. Neurosci. 9, 268–275 (2006).

    CAS  PubMed  Google Scholar 

  108. 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 

  109. Bachstetter, A. D. et al. Fractalkine and CX 3 CR1 regulate hippocampal neurogenesis in adult and aged rats. Neurobiol. Aging 32, 2030–2044 (2011).

    CAS  PubMed  Google Scholar 

  110. 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 

  111. Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290 (2017).This study utilizes unbiased single-cell RNA-sequencing analysis to define DAM microglia.

    CAS  PubMed  Google Scholar 

  112. Wlodarczyk, A. et al. A novel microglial subset plays a key role in myelinogenesis in developing brain. EMBO J. 36, 3292–3308 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Butovsky, O. et al. Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol. Cell. Neurosciences 31, 149–160 (2006).

    CAS  Google Scholar 

  114. Moore, C. S. et al. P2Y12 expression and function in alternatively activated human microglia. Neurol. Neuroimmunol. Neuroinflamm. 2, e80 (2015).

    PubMed  PubMed Central  Google Scholar 

  115. Riazi, K. et al. Microglia-dependent alteration of glutamatergic synaptic transmission and plasticity in the hippocampus during peripheral inflammation. J. Neurosci. 35, 4942–4952 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Naj, A. C. et al. Effects of multiple genetic loci on age at onset in late-onset Alzheimer disease: a genome-wide association study. JAMA Neurol. 71, 1394–1404 (2014).

    PubMed  PubMed Central  Google Scholar 

  117. O’Connell, R. M. et al. MicroRNA-155 promotes autoimmune inflammation by enhancing inflammatory T cell development. Immunity 33, 607–619 (2010).

    PubMed  PubMed Central  Google Scholar 

  118. Streit, W. J., Sammons, N. W., Kuhns, A. J. & Sparks, D. L. Dystrophic microglia in the aging human brain. Glia 45, 208–212 (2004).

    PubMed  Google Scholar 

  119. Streit, W. J. Microglial senescence: does the brain’s immune system have an expiration date? Trends Neurosciences 29, 506–510 (2006).References 118 and 119 propose that microglial senescence is important for age-related decline in cognitive function.

    CAS  Google Scholar 

  120. Flanary, B. E., Sammons, N. W., Nguyen, C., Walker, D. & Streit, W. J. Evidence that aging and amyloid promote microglial cell senescence. Rejuven. Res. 10, 61–74 (2007).

    CAS  Google Scholar 

  121. Verheijden, S. et al. Identification of a chronic non-neurodegenerative microglia activation state in a mouse model of peroxisomal beta-oxidation deficiency. Glia 63, 1606–1620 (2015).

    PubMed  PubMed Central  Google Scholar 

  122. McGeer, P. L., Itagaki, S., Tago, H. & McGeer, E. G. Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR. Neurosci. Lett. 79, 195–200 (1987).

    CAS  PubMed  Google Scholar 

  123. Griffin, W. S. et al. Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc. Natl Acad. Sci. USA 86, 7611–7615 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Streit, W. J. Microglia and Alzheimer’s disease pathogenesis. J. Neurosci. Res. 77, 1–8 (2004).

    CAS  PubMed  Google Scholar 

  125. Streit, W. J., Mrak, R. E. & Griffin, W. S. Microglia and neuroinflammation: a pathological perspective. J. Neuroinflamm. 1, 14 (2004).

    Google Scholar 

  126. 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 

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

    CAS  PubMed  Google Scholar 

  128. 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 

  129. Bennett, C. et al. Evidence that the APOE locus influences rate of disease progression in late onset familial Alzheimer’s disease but is not causative. Am. J. Med. Genet. 60, 1–6 (1995).

    CAS  PubMed  Google Scholar 

  130. Slooter, A. J. et al. Risk estimates of dementia by apolipoprotein E genotypes from a population-based incidence study: the Rotterdam study. Arch. Neurol. 55, 964–968 (1998).

    CAS  PubMed  Google Scholar 

  131. Blacker, D. et al. ApoE-4 and age at onset of Alzheimer’s disease: the NIMH genetics initiative. Neurology 48, 139–147 (1997).

    CAS  PubMed  Google Scholar 

  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. 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 

  134. Bradshaw, E. M. et al. CD33 Alzheimer’s disease locus: altered monocyte function and amyloid biology. Nat. Neurosci. 16, 848–850 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Huang, K. L. et al. A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer’s disease. Nat. Neurosci. 20, 1052–1061 (2017).This study implicates innate immunity in AD through alteration of PU.1 core transcriptional regulation of microglia and blood monocytes.

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Chapuis, J. et al. Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology. Mol. Psychiatry 18, 1225–1234 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Thambisetty, M. et al. Effect of complement CR1 on brain amyloid burden during aging and its modification by APOE genotype. Biol. Psychiatry 73, 422–428 (2013).

    CAS  PubMed  Google Scholar 

  138. 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 

  139. Kamphuis, W., Kooijman, L., Schetters, S., Orre, M. & Hol, E. M. Transcriptional profiling of CD11c-positive microglia accumulating around amyloid plaques in a mouse model for Alzheimer’s disease. Biochim. Biophys. Acta 1862, 1847–1860 (2016).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  141. Srinivasan, K. et al. Untangling the brain’s neuroinflammatory and neurodegenerative transcriptional responses. Nat. Commun. 7, 11295 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Mathys, H. et al. Temporal tracking of microglia activation in neurodegeneration at single-cell resolution. Cell Rep. 21, 366–380 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Hoeijmakers, L., Heinen, Y., van Dam, A. M., Lucassen, P. J. & Korosi, A. Microglial priming and Alzheimer’s disease: a possible role for (early) immune challenges and epigenetics? Front. Hum. Neurosci. 10, 398 (2016).

    PubMed  PubMed Central  Google Scholar 

  144. 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).

    CAS  PubMed  Google Scholar 

  145. Streit, W. J., Braak, H., Xue, Q. S. & Bechmann, I. Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer’s disease. Acta Neuropathol. 118, 475–485 (2009).

    PubMed  PubMed Central  Google Scholar 

  146. Sastre, M., Klockgether, T. & Heneka, M. T. Contribution of inflammatory processes to Alzheimer’s disease: molecular mechanisms. Int. J. Dev. Neurosci. 24, 167–176 (2006).

    CAS  PubMed  Google Scholar 

  147. Perry, V. H., Cunningham, C. & Holmes, C. Systemic infections and inflammation affect chronic neurodegeneration. Nat. Rev. Immunol. 7, 161–167 (2007).

    CAS  PubMed  Google Scholar 

  148. Rojo, L. E., Fernandez, J. A., Maccioni, A. A., Jimenez, J. M. & Maccioni, R. B. Neuroinflammation: implications for the pathogenesis and molecular diagnosis of Alzheimer’s disease. Arch. Med. Res. 39, 1–16 (2008).

    CAS  PubMed  Google Scholar 

  149. Heneka, M. T. et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 14, 388–405 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Liddelow, S. A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017).This study shows that classically activated neuroinflammatory microglia induce toxic astrocytes, which contribute to the death of neurons and oligodendrocytes in neurodegenerative disorders.

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Hametner, S. et al. Iron and neurodegeneration in the multiple sclerosis brain. Ann. Neurol. 74, 848–861 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Dal-Bianco, A. et al. Slow expansion of multiple sclerosis iron rim lesions: pathology and 7 T magnetic resonance imaging. Acta Neuropathol. 133, 25–42 (2017).

    CAS  PubMed  Google Scholar 

  153. Kobayashi, K. et al. Minocycline selectively inhibits M1 polarization of microglia. Cell Death Dis. 4, e525 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Sriram, K., Miller, D. B. & O’Callaghan, J. P. Minocycline attenuates microglial activation but fails to mitigate striatal dopaminergic neurotoxicity: role of tumor necrosis factor-alpha. J. Neurochem. 96, 706–718 (2006).

    CAS  PubMed  Google Scholar 

  155. Ledeboer, A. et al. Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation. Pain 115, 71–83 (2005).

    CAS  PubMed  Google Scholar 

  156. Metz, L. M. & Eliasziw, M. Trial of minocycline in clinically isolated syndrome of multiple sclerosis. N. Engl. J. Med. 377, 789 (2017).

    PubMed  Google Scholar 

  157. Gordon, P. H. et al. Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. Lancet Neurol. 6, 1045–1053 (2007).

    CAS  PubMed  Google Scholar 

  158. Kim, C. et al. Neuron-released oligomeric alpha-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia. Nat. Commun. 4, 1562 (2013).

    PubMed  Google Scholar 

  159. Sanchez-Guajardo, V., Annibali, A., Jensen, P. H. & Romero-Ramos, M. alpha-Synuclein vaccination prevents the accumulation of parkinson disease-like pathologic inclusions in striatum in association with regulatory T cell recruitment in a rat model. J. Neuropathol. Exp. Neurol. 72, 624–645 (2013).

    CAS  PubMed  Google Scholar 

  160. Joers, V., Tansey, M. G., Mulas, G. & Carta, A. R. Microglial phenotypes in Parkinson’s disease and animal models of the disease. Prog. Neurobiol. 155, 57–75 (2017).

    CAS  PubMed  Google Scholar 

  161. Koshimori, Y. et al. Imaging striatal microglial activation in patients with Parkinson’s disease. PLOS ONE 10, e0138721 (2015).

    PubMed  PubMed Central  Google Scholar 

  162. Sampson, T. R. et al. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell 167, 1469–1480 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Parikshak, N. N. et al. Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism. Nature 540, 423–427 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. 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  Google Scholar 

  165. Friedman, B. A. et al. Diverse brain myeloid expression profiles reveal distinct microglial activation states and aspects of Alzheimer’s disease not evident in mouse models. Cell Rep. 22, 832–847 (2018).

    CAS  PubMed  Google Scholar 

  166. Wang, Y. et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model. Cell 160, 1061–1071 (2015).This study demonstrates that microglial TREM2 is a sensor for lipids associated with fibrillar Aβ and its loss affects microglia and augments Aβ accumulation.

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Zheng, H. et al. TREM2 Promotes Microglial Survival by Activating Wnt/beta-Catenin Pathway. J. Neurosci. 37, 1772–1784 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Mazaheri, F. et al. TREM2 deficiency impairs chemotaxis and microglial responses to neuronal injury. EMBO Rep. 18, 1186–1198 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Song, W. M. et al. Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism. J. Exp. Med. 215, 745–760 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Piccio, L. et al. Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status. Acta Neuropathol. 131, 925–933 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Klesney-Tait, J., Turnbull, I. R. & Colonna, M. The TREM receptor family and signal integration. Nat. Immunol. 7, 1266–1273 (2006).

    CAS  PubMed  Google Scholar 

  172. Piccio, L. et al. Blockade of TREM-2 exacerbates experimental autoimmune encephalomyelitis. Eur. J. Immunol. 37, 1290–1301 (2007).

    CAS  PubMed  Google Scholar 

  173. Jay, T. R. et al. TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models. J. Exp. Med. 212, 287–295 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. 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 

  175. Jay, T. R. et al. Disease progression-dependent effects of TREM2 deficiency in a mouse model of Alzheimer’s disease. J. Neurosci. 37, 637–647 (2017).References 173–175 show time-dependent differential effects of TREM2-dependent microglial function in AD mouse models.

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Abduljaleel, Z. et al. Evidence of trem2 variant associated with triple risk of Alzheimer’s disease. PLOS ONE 9, e92648 (2014).

    PubMed  PubMed Central  Google Scholar 

  177. Jin, S. C. et al. TREM2 is associated with increased risk for Alzheimer’s disease in African Americans. Mol. Neurodegener. 10, 19 (2015).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  179. Atagi, Y. et al. Apolipoprotein E is a ligand for triggering receptor expressed on myeloid cells 2 (TREM2). J. Biol. Chem. 290, 26043–26050 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. 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-beta by microglia. Neuron 91, 328–340 (2016).References 179 and 180 find that ApoE binds to TREM2 and may thus explain the functional relevance of two AD-associated risk factors.

    CAS  PubMed  Google Scholar 

  181. Bailey, C. C., DeVaux, L. B. & Farzan, M. The triggering receptor expressed on myeloid cells 2 binds apolipoprotein. J. Biol. Chem. 290, 26033–26042 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Shi, Y. et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549, 523–527 (2017).

    PubMed  PubMed Central  Google Scholar 

  183. Leyns, C. E. G. et al. TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy. Proc. Natl Acad. Sci. USA 114, 11524–11529 (2017).References 182 and 183 connect TREM2 and ApoE signalling with exacerbation of neuroinflammation and tauopathy.

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Venegas, C. et al. Microglia-derived ASC specks cross-seed amyloid-beta in Alzheimer’s disease. Nature 552, 355–361 (2017).

    CAS  PubMed  Google Scholar 

  185. Spangenberg, E. E. et al. Eliminating microglia in Alzheimer’s mice prevents neuronal loss without modulating amyloid-beta pathology. Brain 139, 1265–1281 (2016).

    PubMed  PubMed Central  Google Scholar 

  186. Sosna, J. et al. Early long-term administration of the CSF1R inhibitor PLX3397 ablates microglia and reduces accumulation of intraneuronal amyloid, neuritic plaque deposition and pre-fibrillar oligomers in 5XFAD mouse model of Alzheimer’s disease. Mol. Neurodegener. 13, 11 (2018).

    PubMed  PubMed Central  Google Scholar 

  187. Gomez-Nicola, D., Fransen, N. L., Suzzi, S. & Perry, V. H. Regulation of microglial proliferation during chronic neurodegeneration. J. Neurosci. 33, 2481–2493 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. 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).This report shows rapid repopulation of microglia following pharmacological depletion.

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Dagher, N. N. et al. Colony-stimulating factor 1 receptor inhibition prevents microglial plaque association and improves cognition in 3xTg-AD mice. J. Neuroinflamm. 12, 139 (2015).

    Google Scholar 

  190. Olmos-Alonso, A. et al. Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer’s-like pathology. Brain 139, 891–907 (2016).

    PubMed  PubMed Central  Google Scholar 

  191. Dheen, S. T., Kaur, C. & Ling, E. A. Microglial activation and its implications in the brain diseases. Curr. Med. Chem. 14, 1189–1197 (2007).

    CAS  PubMed  Google Scholar 

  192. Lleo, A., Galea, E. & Sastre, M. Molecular targets of non-steroidal anti-inflammatory drugs in neurodegenerative diseases. Cell. Mol. Life Sci. 64, 1403–1418 (2007).

    CAS  PubMed  Google Scholar 

  193. Liao, F. et al. Anti-ApoE antibody given after plaque onset decreases Abeta accumulation and improves brain function in a mouse model of Abeta amyloidosis. J. Neurosci. 34, 7281–7292 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  194. Sevigny, J. et al. The antibody aducanumab reduces Aß plaques in Alzheimer’s disease. Nature 537, 50–56 (2016).

    CAS  PubMed  Google Scholar 

  195. Koval, E. D. et al. Method for widespread microRNA-155 inhibition prolongs survival in ALS-model mice. Hum. Mol. Genet. 22, 4127–4135 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. Ponomarev, E. D., Veremeyko, T., Barteneva, N., Krichevsky, A. M. & Weiner, H. L. MicroRNA-124 promotes microglia quiescence and suppresses EAE by deactivating macrophages via the C/EBP-alpha-PU.1 pathway. Nat. Med. 17, 64–70 (2011).

    CAS  PubMed  Google Scholar 

  197. Lazarov, O. et al. Environmental enrichment reduces Abeta levels and amyloid deposition in transgenic mice. Cell 120, 701–713 (2005).

    CAS  PubMed  Google Scholar 

  198. Xu, H. et al. Environmental enrichment potently prevents microglia-mediated neuroinflammation by human amyloid ß-protein oligomers. J. Neurosci. 36, 9041–9056 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Erny, D. et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat. Neurosci. 18, 965–977 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. Thion, M. S. et al. Microbiome influences prenatal and adult microglia in a sex-specific manner. Cell 172, 500–516 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  201. Vogt, N. M. et al. Gut microbiome alterations in Alzheimer’s disease. Scientif. Rep. 7, 13537 (2017).

    Google Scholar 

  202. Jangi, S. et al. Alterations of the human gut microbiome in multiple sclerosis. Nat. Commun. 7, 12015 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Bakshi, R. et al. MRI in multiple sclerosis: current status and future prospects. Lancet. Neurol. 7, 615–625 (2008).

    PubMed  PubMed Central  Google Scholar 

  204. Johnson, K. A., Fox, N. C., Sperling, R. A. & Klunk, W. E. Brain imaging in Alzheimer disease. Cold Spring Harb. Perspect. Med. 2, a006213 (2012).

    PubMed  PubMed Central  Google Scholar 

  205. Nimmerjahn, A. Two-photon imaging of microglia in the mouse cortex in vivo. Cold Spring Harb. Protoc. https://doi.org/10.1101/pdb.prot069294 (2012).

    Article  PubMed  Google Scholar 

  206. Dupont, A. C. et al. Translocator protein-18 kDa (TSPO) positron emission tomography (PET) imaging and its clinical impact in neurodegenerative diseases. Int. J. Mol. Sci. https://doi.org/10.3390/ijms18040785 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  207. Ghadery, C. et al. Microglial activation in Parkinson’s disease using [18F]-FEPPA. J. Neuroinflamm. 14, 8 (2017).

    Google Scholar 

  208. Cerami, C., Iaccarino, L. & Perani, D. Molecular imaging of neuroinflammation in neurodegenerative dementias: the role of in vivo PET imaging. Int. J. Mol. Sci. FF (2017).

  209. Hamelin, L. et al. Early and protective microglial activation in Alzheimer’s disease: a prospective study using 18F-DPA-714 PET imaging. Brain 139, 1252–1264 (2016).

    PubMed  Google Scholar 

  210. Politis, M., Su, P. & Piccini, P. Imaging of microglia in patients with neurodegenerative disorders. Front. Pharmacol. 3, 96 (2012).

    PubMed  PubMed Central  Google Scholar 

  211. Brendel, M. et al. Increase of TREM2 during aging of an Alzheimer’s disease mouse model is paralleled by microglial activation and amyloidosis. Front. Aging Neurosci. 9, 8 (2017).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  213. 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  Google Scholar 

  214. Takata, K. et al. Induced-pluripotent-stem-cell-derived primitive macrophages provide a platform for modeling tissue-resident macrophage differentiation and function. Immunity 47, 183–198 (2017).

    CAS  PubMed  Google Scholar 

  215. 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 

  216. Kierdorf, K. & Prinz, M. Factors regulating microglia activation. Front. Cell. Neurosci. 7, 44 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  217. 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 

  218. Matyash, M., Zabiegalov, O., Wendt, S., Matyash, V. & Kettenmann, H. The adenosine generating enzymes CD39/CD73 control microglial processes ramification in the mouse brain. PLOS ONE 12, e0175012 (2017).

    PubMed  PubMed Central  Google Scholar 

  219. Lanser, A. J. et al. Disruption of the ATP/adenosine balance in CD39(−/−) mice is associated with handling-induced seizures. Immunology 152, 589–601 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  220. Bennett, F. C. et al. A combination of ontogeny and CNS environment establishes microglial identity. Neuron 98, 1170–1183 (2018).This study shows that transplanted macrophages from multiple tissues can express microglial genes in the brain; however, only those of yolk sac origin fully attain microglial identity.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

O.B. is supported by the US National Institutes of Health (NIH) National Institute of Neurological Disorders and Stroke (R01 NS088137, R21 NS104609 and R21 NS101673), National Institute on Aging (NIA; R01 AG051812 and R01 AG054672) and National Eye Institute (R01 EY027921); the National Multiple Sclerosis Society (5092A1); a Nancy Davis Foundation Faculty Award; a Cure Alzheimer’s Fund Award; the Amyotrophic Lateral Sclerosis Association; and Sanofi. H.L.W. is supported by the US Department of Defense (AL120029), the Thome Foundation and the NIH NIA (R01AG043975 and R01AG040092).

Reviewer information

Nature Reviews Neuroscience thanks B. Eggen, M. Prinz and M.-E. Tremblay for their contribution to the peer review of this work.

Author information

Authors and Affiliations

  1. Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Oleg Butovsky & Howard L. Weiner

Authors
  1. Oleg Butovsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Howard L. Weiner
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

O.B. and H.L.W. researched data for the article, made substantial contributions to the discussion of content, wrote the article and reviewed and/or edited the manuscript before submission.

Corresponding authors

Correspondence to Oleg Butovsky or Howard L. Weiner.

Ethics declarations

Competing interests

O.B. and H.L.W. hold patent applications entitled ‘Targeting Apolipoprotein E (APOE) in Neurologic Disease’ (PCT/US2015/056492), ‘Micrornas in Neurodegenerative Disorders’ (PCT/US2012/059671) and ‘Mir-155 Inhibitors for Treating Amyotrophic Lateral Sclerosis (ALS)’ (Application #20180161357), which have exclusive licensing rights from the Brigham and Women’s Hospital. O.B. is an adviser and collaborator for Sanofi and Nanostring.

Additional information

Publisher’s note

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

Glossary

Monocytes

Mononuclear cells that are derived from the bone marrow and circulate in the bloodstream. They pass into the body tissues, where they differentiate into various types of macrophages.

Tissue macrophages

Tissue-resident macrophages that are distributed throughout the body, including microglia, liver Kupffer cells, lung alveolar cells and splenic and peritoneal macrophages. They are established before birth and maintain themselves during adulthood independent of replenishment by blood monocytes. They become mobile when stimulated by inflammation and migrate to affected areas.

Cytokines

Proteins secreted by a cell that act in a paracrine or autocrine fashion and affect the behaviour of other cells.

RNA-sequencing

An unbiased whole transcriptome deep-sequencing technology that uses next-generation sequencing to detect novel or known features and to quantify RNA activity.

Epigenetic studies

Investigations of inheritance by mechanisms other than those that involve changes to the underlying DNA sequence. Types of epigenetic mechanisms include DNA methylation, post-translational histone modifications and non-coding RNAs.

Peripheral myeloid cells

Cells originating from haematopoietic cells, as opposed to tissue-resident myeloid cells, such as microglia.

Induced pluripotent stem cells

(iPSCs). Stem cells derived from skin or blood that have been reprogrammed into an embryonic-like pluripotent state.

Enhancers

Short regions of DNA, typically occupied by multiple transcription factors, that are sufficient to drive expression of a gene with temporal and/or cell-type specificity.

Lineage-determining transcription factor

(LDTF). Transcription factors that create regions of open chromatin, which enables the recruitment of secondary transcription factors required for cell-type-specific gene expression.

Environmental enrichment

Creation of complex environmental stimulation through the use of toys, ladders, tunnels and a running wheel in the environment in which animals are housed.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Butovsky, O., Weiner, H.L. Microglial signatures and their role in health and disease. Nat Rev Neurosci 19, 622–635 (2018). https://doi.org/10.1038/s41583-018-0057-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41583-018-0057-5

This article is cited by

Search

Advanced 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