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Microglial immune checkpoint mechanisms

Nature Neurosciencevolume 21pages779786 (2018) | Download Citation


Microglia differentiate from progenitors that infiltrate the nascent CNS during early embryonic development. They then remain in this unique immune-privileged environment throughout life. Multiple immune mechanisms, which we collectively refer to as microglial checkpoints, ensure efficient and tightly regulated microglial responses to perturbations in the CNS milieu. Such mechanisms are essential for proper CNS development and optimal physiological function. However, in chronic disease or aging, when a robust immune response is required, such checkpoint mechanisms may limit the ability of microglia to protect the CNS. Here we survey microglial checkpoint mechanisms and their roles in controlling microglial function throughout life and in disease, and discuss how they may be targeted therapeutically.

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  • 25 June 2018

    In the version of this article initially published, the annotation accompanying ref. 47 ended with “though the modulation of microglia.” The first word of this phrase should have been “through.” The error has been corrected in the HTML and PDF versions of the article.


  1. 1.

    Matzinger, P. & Kamala, T. Tissue-based class control: the other side of tolerance. Nat. Rev. Immunol. 11, 221–230 (2011).

  2. 2.

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

  3. 3.

    Ajami, B., Bennett, J. L., Krieger, C., Tetzlaff, W. & Rossi, F. M. V. Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat. Neurosci. 10, 1538–1543 (2007). This study showed that blood-derived cells do not contribute to the microglial pool.

  4. 4.

    Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010). This paper showed that microglia originate from the yolk sac-derived progenitors.

  5. 5.

    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 identified several microglia-specific genes.

  6. 6.

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

  7. 7.

    Gosselin, D. et al. Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell 159, 1327–1340 (2014). Refs. 6 and 7 independently showed the key role of environmental signals is shaping the epigenetic and transcriptomic signatures of various macrophage subtypes (including microglia).

  8. 8.

    Nimmerjahn, A., Kirchhoff, F. & Helmchen, F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 1314–1318 (2005). This paper revealed that microglial processes constantly scan their environment.

  9. 9.

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

  10. 10.

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

  11. 11.

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

  12. 12.

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

  13. 13.

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

  14. 14.

    Olde Nordkamp, M. J., Koeleman, B. P. & Meyaard, L. Do inhibitory immune receptors play a role in the etiology of autoimmune disease? Clin. Immunol. 150, 31–42 (2014).

  15. 15.

    Harrison-Brown, M., Liu, G. J. & Banati, R. Checkpoints to the brain: directing myeloid cell migration to the central nervous system. Int. J. Mol. Sci. 17, 2030 (2016).

  16. 16.

    Shechter, R., London, A. & Schwartz, M. Orchestrated leukocyte recruitment to immune-privileged sites: absolute barriers versus educational gates. Nat. Rev. Immunol. 13, 206–218 (2013). This reviews the immune environment of the borders of the CNS and other immune-privileged tissues.

  17. 17.

    Gadani, S. P., Smirnov, I., Smith, A. T., Overall, C. C. & Kipnis, J. Characterization of meningeal type 2 innate lymphocytes and their response to CNS injury. J. Exp. Med. 214, 285–296 (2017).

  18. 18.

    Goldmann, T. et al. Origin, fate and dynamics of macrophages at central nervous system interfaces. Nat. Immunol. 17, 797–805 (2016).

  19. 19.

    Goldmann, T. & Prinz, M. Role of microglia in CNS autoimmunity. Clin. Dev. Immunol. 2013, 208093 (2013).

  20. 20.

    Mracsko, E. & Veltkamp, R. Neuroinflammation after intracerebral hemorrhage. Front. Cell. Neurosci. 8, 388 (2014).

  21. 21.

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

  22. 22.

    Brionne, T. C., Tesseur, I., Masliah, E. & Wyss-Coray, T. Loss of TGF-β 1 leads to increased neuronal cell death and microgliosis in mouse brain. Neuron 40, 1133–1145 (2003).

  23. 23.

    Zhao, X. et al. Neuronal interleukin-4 as a modulator of microglial pathways and ischemic brain damage. J. Neurosci. 35, 11281–11291 (2015).

  24. 24.

    Shin, W. H. et al. Microglia expressing interleukin-13 undergo cell death and contribute to neuronal survival in vivo. Glia 46, 142–152 (2004).

  25. 25.

    Neumann, H., Misgeld, T., Matsumuro, K. & Wekerle, H. Neurotrophins inhibit major histocompatibility class II inducibility of microglia: involvement of the p75 neurotrophin receptor. Proc. Natl Acad. Sci. USA 95, 5779–5784 (1998).

  26. 26.

    Lee, M. Neurotransmitters and microglial-mediated neuroinflammation. Curr. Protein Pept. Sci. 14, 21–32 (2013).

  27. 27.

    Taylor, D. L., Diemel, L. T., Cuzner, M. L. & Pocock, J. M. Activation of group II metabotropic glutamate receptors underlies microglial reactivity and neurotoxicity following stimulation with chromogranin A, a peptide up-regulated in Alzheimer’s disease. J. Neurochem. 82, 1179–1191 (2002).

  28. 28.

    Taylor, D. L., Diemel, L. T. & Pocock, J. M. Activation of microglial group III metabotropic glutamate receptors protects neurons against microglial neurotoxicity. J. Neurosci. 23, 2150–2160 (2003).

  29. 29.

    McCluskey, L. P. & Lampson, L. A. Local immune regulation in the central nervous system by substance P vs. glutamate. J. Neuroimmunol. 116, 136–146 (2001).

  30. 30.

    Pocock, J. M. & Kettenmann, H. Neurotransmitter receptors on microglia. Trends Neurosci. 30, 527–535 (2007).

  31. 31.

    Biber, K., Neumann, H., Inoue, K. & Boddeke, H. W. Neuronal ‘On’ and ‘Off’ signals control microglia. Trends Neurosci. 30, 596–602 (2007).

  32. 32.

    Neumann, H., Boucraut, J., Hahnel, C., Misgeld, T. & Wekerle, H. Neuronal control of MHC class II inducibility in rat astrocytes and microglia. Eur. J. Neurosci. 8, 2582–2590 (1996).

  33. 33.

    Harrison, J. K. et al. Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia. Proc. Natl Acad. Sci. USA 95, 10896–10901 (1998).

  34. 34.

    Garton, K. J. et al. Tumor necrosis factor-α-converting enzyme (ADAM17) mediates the cleavage and shedding of fractalkine (CX3CL1). J. Biol. Chem. 276, 37993–38001 (2001).

  35. 35.

    Maggi, L. et al. CX3CR1 deficiency alters hippocampal-dependent plasticity phenomena blunting the effects of enriched environment. Front. Cell. Neurosci. 5, 22 (2011).

  36. 36.

    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).

  37. 37.

    Rogers, J. T. et al. CX3CR1 deficiency leads to impairment of hippocampal cognitive function and synaptic plasticity. J. Neurosci. 31, 16241–16250 (2011).

  38. 38.

    Lee, S. et al. CX3CR1 deficiency alters microglial activation and reduces beta-amyloid deposition in two Alzheimer’s disease mouse models. Am. J. Pathol. 177, 2549–2562 (2010). This paper was the first to propose CX3CR1 as a therapeutic target in Alzheimer disease.

  39. 39.

    Liu, Z., Condello, C., Schain, A., Harb, R. & Grutzendler, J. CX3CR1 in microglia regulates brain amyloid deposition through selective protofibrillar amyloid-β phagocytosis. J. Neurosci. 30, 17091–17101 (2010).

  40. 40.

    Walker, D. G. & Lue, L.-F. Understanding the neurobiology of CD200 and the CD200 receptor: a therapeutic target for controlling inflammation in human brains? Future Neurol. 8, 321–332 (2013).

  41. 41.

    Barclay, A. N., Wright, G. J., Brooke, G. & Brown, M. H. CD200 and membrane protein interactions in the control of myeloid cells. Trends Immunol. 23, 285–290 (2002).

  42. 42.

    Cohen, M. et al. Newly-formed endothelial cells regulate myeloid cell activity following spinal cord injury via expression of CD200 ligand. J. Neurosci. 37, 972–985 (2017).

  43. 43.

    Mott, R. T. et al. Neuronal expression of CD22: novel mechanism for inhibiting microglial proinflammatory cytokine production. Glia 46, 369–379 (2004).

  44. 44.

    Gitik, M., Liraz-Zaltsman, S., Oldenborg, P.-A., Reichert, F. & Rotshenker, S. Myelin down-regulates myelin phagocytosis by microglia and macrophages through interactions between CD47 on myelin and SIRPα (signal regulatory protein-α) on phagocytes. J. Neuroinflammation 8, 24 (2011).

  45. 45.

    Junker, A. et al. MicroRNA profiling of multiple sclerosis lesions identifies modulators of the regulatory protein CD47. Brain 132, 3342–3352 (2009).

  46. 46.

    Matcovitch-Natan, O. et al. Microglia development follows a stepwise program to regulate brain homeostasis. Science 353, aad8670 (2016). This paper follows the transcriptional and epigenetic profile of microglia throughout development.

  47. 47.

    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). This study showed that aging-induced secretory phenotype of the blood–cerebrospinal fluid barrier negatively affects cognitive ability through the modulation of microglia.

  48. 48.

    Cronk, J. C. et al. Methyl-CpG binding protein 2 regulates microglia and macrophage gene expression in response to inflammatory stimuli. Immunity 42, 679–691 (2015).

  49. 49.

    Kelly, L. M., Englmeier, U., Lafon, I., Sieweke, M. H. & Graf, T. MafB is an inducer of monocytic differentiation. EMBO J. 19, 1987–1997 (2000).

  50. 50.

    Potthoff, M. J. & Olson, E. N. MEF2: a central regulator of diverse developmental programs. Development 134, 4131–4140 (2007).

  51. 51.

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

  52. 52.

    Reemst, K., Noctor, S. C., Lucassen, P. J. & Hol, E. M. The indispensable roles of microglia and astrocytes during brain development. Front. Hum. Neurosci. 10, 566 (2016).

  53. 53.

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

  54. 54.

    Aarum, J., Sandberg, K., Haeberlein, S. L. B. & Persson, M. A. A. Migration and differentiation of neural precursor cells can be directed by microglia. Proc. Natl Acad. Sci. USA 100, 15983–15988 (2003).

  55. 55.

    Estes, M. L. & McAllister, A. K. Maternal immune activation: implications for neuropsychiatric disorders. Science 353, 772–777 (2016).

  56. 56.

    Knuesel, I. et al. Maternal immune activation and abnormal brain development across CNS disorders. Nat. Rev. Neurol. 10, 643–660 (2014).

  57. 57.

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

  58. 58.

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

  59. 59.

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

  60. 60.

    Toth, A. B. et al. Synapse maturation by activity-dependent ectodomain shedding of SIRPα. Nat. Neurosci. 16, 1417–1425 (2013).

  61. 61.

    Derecki, N. C. et al. Wild-type microglia arrest pathology in a mouse model of Rett syndrome. Nature 484, 105–109 (2012).

  62. 62.

    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).

  63. 63.

    Schafer, D. P. et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74, 691–705 (2012).

  64. 64.

    Sellner, S. et al. Microglial CX3CR1 promotes adult neurogenesis by inhibiting Sirt 1/p65 signaling independent of CX3CL1. Acta Neuropathol. Commun. 4, 102 (2016).

  65. 65.

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

  66. 66.

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

  67. 67.

    Tasic, B. et al. Adult mouse cortical cell taxonomy revealed by single cell transcriptomics. Nat. Neurosci. 19, 335–346 (2016).

  68. 68.

    Lake, B. B. et al. Neuronal subtypes and diversity revealed by single-nucleus RNA sequencing of the human brain. Science 352, 1586–1590 (2016).

  69. 69.

    Zhang, Y. & Barres, B. A. Astrocyte heterogeneity: an underappreciated topic in neurobiology. Curr. Opin. Neurobiol. 20, 588–594 (2010).

  70. 70.

    Kim, K.-W. et al. In vivo structure/function and expression analysis of the CX3C chemokine fractalkine. Blood 118, e156–e167 (2011).

  71. 71.

    Norden, D. M., Fenn, A. M., Dugan, A. & Godbout, J. P. TGFβ produced by IL-10 redirected astrocytes attenuates microglial activation. Glia 62, 881–895 (2014).

  72. 72.

    Lyons, A. et al. CD200 ligand receptor interaction modulates microglial activation in vivo and in vitro: a role for IL-4. J. Neurosci. 27, 8309–8313 (2007).

  73. 73.

    Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290 (2017). This study identified the transcriptional signature of microglia associated with Aβ plaques in a mouse model of Alzheimer’s disease.

  74. 74.

    Füger, P. et al. Microglia turnover with aging and in an Alzheimer’s model via long-term in vivo single-cell imaging. Nat. Neurosci. 20, 1371–1376 (2017). This work revealed the extreme longevity of microglia in mice.

  75. 75.

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

  76. 76.

    Morrison, J. H. & Baxter, M. G. The ageing cortical synapse: hallmarks and implications for cognitive decline. Nat. Rev. Neurosci. 13, 240–250 (2012).

  77. 77.

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

  78. 78.

    Cox, F. F., Carney, D., Miller, A.-M. & Lynch, M. A. CD200 fusion protein decreases microglial activation in the hippocampus of aged rats. Brain Behav. Immun. 26, 789–796 (2012).

  79. 79.

    Pabon, M. M., Bachstetter, A. D., Hudson, C. E., Gemma, C. & Bickford, P. C. CX3CL1 reduces neurotoxicity and microglial activation in a rat model of Parkinson’s disease. J. Neuroinflammation 8, 9 (2011).

  80. 80.

    Baruch, K. et al. Aging. Aging-induced type I interferon response at the choroid plexus negatively affects brain function. Science 346, 89–93 (2014).

  81. 81.

    Liu, C. et al. Macrophages mediate the repair of brain vascular rupture through direct physical adhesion and mechanical traction. Immunity 44, 1162–1176 (2016). This study demonstrated that cerebrovascular ruptures could be directly repaired by microglia.

  82. 82.

    Koizumi, S. et al. UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis. Nature 446, 1091–1095 (2007).

  83. 83.

    London, A., Cohen, M. & Schwartz, M. Microglia and monocyte-derived macrophages: functionally distinct populations that act in concert in CNS plasticity and repair. Front. Cell. Neurosci. 7, 34 (2013).

  84. 84.

    Lai, A. Y. & McLaurin, J. Clearance of amyloid-β peptides by microglia and macrophages: the issue of what, when and where. Future Neurol 7, 165–176 (2012).

  85. 85.

    Bhaskar, K. et al. Regulation of tau pathology by the microglial fractalkine receptor. Neuron 68, 19–31 (2010).

  86. 86.

    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).

  87. 87.

    Sanjana, N. E. Genome-scale CRISPR pooled screens. Anal. Biochem. 532, 95–99 (2017).

  88. 88.

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

  89. 89.

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

  90. 90.

    Xanthos, D. N. & Sandkühler, J. Neurogenic neuroinflammation: inflammatory CNS reactions in response to neuronal activity. Nat. Rev. Neurosci. 15, 43–53 (2014).

  91. 91.

    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).

  92. 92.

    Shechter, R. et al. Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice. PLoS Med. 6, e1000113 (2009). This paper showed distinct and nonredundant roles of microglia and infiltrating macrophages in CNS pathology.

  93. 93.

    Gosselin, D. et al. An environment-dependent transcriptional network specifies human microglia identity. Science 356, eaal3222 (2017). This work compared expression of orthologous genes in human and mouse microglia and demonstrated the effect of culture condition on microglial transcriptional profile.

  94. 94.

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

  95. 95.

    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).

  96. 96.

    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.e186 (2017).

  97. 97.

    Galatro, T. F. et al. Transcriptomic analysis of purified human cortical microglia reveals age-associated changes. Nat. Neurosci. 20, 1162–1171 (2017). This study revealed differences in the expression profile of human and murine microglia and showed that discrepancies between the two increase with aging.

  98. 98.

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

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We thank S. Schwarzbaum for editing the manuscript and G. Brodsky for figure artwork. I.A. is supported by the Chan Zuckerberg Initiative (CZI), an HHMI International Scholar award, European Research Council Consolidator Grant (ERC-COG) 724471-HemTree2.0, an MRA Established Investigator Award (509044), the Israel Science Foundation (703/15), the Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine, a Helen and Martin Kimmel award for innovative investigation, a Minerva Stiftung research grant, the Israeli Ministry of Science, Technology, and Space, the David and Fela Shapell Family Foundation, a NeuroMac DFG/Transregional Collaborative Research Center Grant, and the Abramson Family Center for Young Scientists. M.S. is supported by the Advanced European Research Council (ERC-2016-ADG 741744), the Israel Science Foundation-Legacy Heritage Biomedical Science Partnership-research (grant 1354/15), Israel Science Foundation (grant 991/16), Consolidated Anti-Aging Foundation Chicago (2016-2017) and Adelis Foundation (2018-2021).

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  1. Department of Immunology, Weizmann Institute of Science, Rehovot, Israel

    • Aleksandra Deczkowska
    •  & Ido Amit
  2. Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel

    • Michal Schwartz


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The authors declare no competing financial interests.

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Correspondence to Michal Schwartz.

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