Glial cells are abundant in the CNS and are essential for brain development and homeostasis. These cells also regulate tissue recovery after injury and their dysfunction is a possible contributing factor to neurodegenerative and psychiatric disease. Recent evidence suggests that microglia, which are also the brain’s major resident immune cells, provide disease-modifying regulation of the other major glial populations, namely astrocytes and oligodendrocytes. In addition, peripheral immune cells entering the CNS after injury and in disease may directly affect microglial, astrocyte and oligodendrocyte function, suggesting an integrated network of immune cell–glial cell communication.
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Barres, B. A. The mystery and magic of glia: a perspective on their roles in health and disease. Neuron 60, 430–440 (2008).
Azevedo, F. A. C. et al. Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled-up primate brain. J. Comp. Neurol. 513, 532–541 (2009).
Morest, D. K. & Silver, J. Precursors of neurons, neuroglia, and ependymal cells in the CNS: what are they? Where are they from? How do they get where they are going? Glia 43, 6–18 (2003).
Saunders, A. et al. Molecular diversity and specializations among the cells of the adult mouse brain. Cell 174, 1015–1030 (2018).
Böttcher, C. et al. Human microglia regional heterogeneity and phenotypes determined by multiplexed single-cell mass cytometry. Nat. Neurosci. 22, 78–90 (2019).
Masuda, T. et al. Spatial and temporal heterogeneity of mouse and human microglia at single-cell resolution. Nature 566, 388–392 (2019).
Van Hove, H. et al. A single-cell atlas of mouse brain macrophages reveals unique transcriptional identities shaped by ontogeny and tissue environment. Nat. Neurosci. 22, 1021–1035 (2019).
Grabert, K. et al. Microglial brain region-dependent diversity and selective regional sensitivities to aging. Nat. Neurosci. 19, 504–516 (2016). This was the first study to show microglial heterogeneity across brain regions.
Prinz, M., Erny, D. & Hagemeyer, N. Ontogeny and homeostasis of CNS myeloid cells. Nat. Immunol. 18, 385–392 (2017).
Kipnis, J. Multifaceted interactions between adaptive immunity and the central nervous system. Science 353, 766–771 (2016).
Goldmann, T. et al. Origin, fate and dynamics of macrophages at central nervous system interfaces. Nat. Immunol. 17, 797–805 (2016). This study determined that non-microglial CNS macrophages arise from haematopoietic precursors during embryonic development and establish stable populations, with the notable exception of choroid plexus macrophages.
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). This study provides an excellent description of the different immune cell populations that reside within the CNS using CyTOF.
David, S., Kroner, A., Greenhalgh, A. D., Zarruk, J. G. & López-Vales, R. Myeloid cell responses after spinal cord injury. J. Neuroimmunol. 321, 97–108 (2018).
Herz, J., Filiano, A. J., Smith, A., Yogev, N. & Kipnis, J. Myeloid cells in the central nervous system. Immunity 46, 943–956 (2017).
Filiano, A. J., Gadani, S. P. & Kipnis, J. How and why do T cells and their derived cytokines affect the injured and healthy brain? Nat. Rev. Neurosci. 18, 375–384 (2017).
Kierdorf, K. & Prinz, M. Microglia in steady state. J. Clin. Invest. 127, 3201–3209 (2017).
Pósfai, B., Cserép, C., Orsolits, B. & Dénes, Á. New insights into microglia–neuron interactions: a neuron’s perspective. Neuroscience 405, 103–117 (2019).
Kisler, K., Nelson, A. R., Montagne, A. & Zlokovic, B. V. Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease. Nat. Rev. Neurosci. 18, 419–434 (2017).
Heindryckx, F. & Li, J.-P. Role of proteoglycans in neuro-inflammation and central nervous system fibrosis. Matrix Biol. 68–69, 589–601 (2018).
Valny, M., Honsa, P., Kriska, J. & Anderova, M. Multipotency and therapeutic potential of NG2 cells. Biochem. Pharmacol. 141, 42–55 (2017).
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).
Wohleb, E. S. & Godbout, J. P. Basic aspects of the immunology of neuroinflammation. Mod. Trends Pharmacopsychiatry 28, 1–19 (2013).
Zhou, B., Zuo, Y.-X. & Jiang, R.-T. Astrocyte morphology: diversity, plasticity, and role in neurological diseases. CNS Neurosci. Ther. 25, 665–673 (2019).
Allen, N. J. et al. Astrocyte glypicans 4 and 6 promote formation of excitatory synapses via GluA1 AMPA receptors. Nature 486, 410–414 (2012).
Christopherson, K. S. et al. Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell 120, 421–433 (2005). Together with reference 24, this study demonstrated that astrocyte-secreted factors promote the formation of functional and structural synapses.
Chuquet, J., Quilichini, P., Nimchinsky, E. A. & Buzsáki, G. Predominant enhancement of glucose uptake in astrocytes versus neurons during activation of the somatosensory cortex. J. Neurosci. 30, 15298–15303 (2010).
Ioannou, M. S. et al. Neuron-astrocyte metabolic coupling protects against activity-induced fatty acid toxicity. Cell 177, 1522–1535 (2019).
Magistretti, P. J. & Allaman, I. Lactate in the brain: from metabolic end-product to signalling molecule. Nat. Rev. Neurosci. 19, 235–249 (2018).
Bergles, D. E. & Jahr, C. E. Synaptic activation of glutamate transporters in hippocampal astrocytes. Neuron 19, 1297–1308 (1997).
Hertz, L. Possible role of neuroglia: a potassium-mediated neuronal–neuroglial–neuronal impulse transmission system. Nature 206, 1091–1094 (1965).
Rusakov, D. A. Disentangling calcium-driven astrocyte physiology. Nat. Rev. Neurosci. 16, 226–233 (2015).
Abbott, N. J., Patabendige, A. A. K., Dolman, D. E. M., Yusof, S. R. & Begley, D. J. Structure and function of the blood–brain barrier. Neurobiol. Dis. 37, 13–25 (2010).
Santello, M., Toni, N. & Volterra, A. Astrocyte function from information processing to cognition and cognitive impairment. Nat. Neurosci. 22, 154–166 (2019).
Hastings, M. H., Maywood, E. S. & Brancaccio, M. Generation of circadian rhythms in the suprachiasmatic nucleus. Nat. Rev. Neurosci. 19, 453–469 (2018).
Heneka, M. T., McManus, R. M. & Latz, E. Inflammasome signalling in brain function and neurodegenerative disease. Nat. Rev. Neurosci. 19, 610–621 (2018).
Anderson, M. A. et al. Astrocyte scar formation aids central nervous system axon regeneration. Nature 532, 195–200 (2016).
Bradbury, E. J. et al. Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature 416, 636–640 (2002).
Anderson, M. A. et al. Required growth facilitators propel axon regeneration across complete spinal cord injury. Nature 561, 396–400 (2018).
Boulanger, J. J. & Messier, C. From precursors to myelinating oligodendrocytes: contribution of intrinsic and extrinsic factors to white matter plasticity in the adult brain. Neuroscience 269, 343–366 (2014).
Butt, A. M. in Encyclopedia of Neuroscience (ed. Squire, L. R.) 203–208 (Academic Press, 2009).
Zhu, X., Bergles, D. E. & Nishiyama, A. NG2 cells generate both oligodendrocytes and gray matter astrocytes. Development 135, 145–157 (2008).
Dawson, M. R., Polito, A., Levine, J. M. & Reynolds, R. NG2-expressing glial progenitor cells: an abundant and widespread population of cycling cells in the adult rat CNS. Mol. Cell. Neurosci. 24, 476–488 (2003).
Falcão, A. M. et al. Disease-specific oligodendrocyte lineage cells arise in multiple sclerosis. Nat. Med. 24, 1837–1844 (2018).
Battefeld, A., Klooster, J. & Kole, M. H. P. Myelinating satellite oligodendrocytes are integrated in a glial syncytium constraining neuronal high-frequency activity. Nat. Commun. 7, 11298–11298 (2016).
Niu, J. et al. Aberrant oligodendroglial–vascular interactions disrupt the blood–brain barrier, triggering CNS inflammation. Nat. Neurosci. 22, 709–718 (2019).
Greter, M., Lelios, I. & Croxford, A. L. Microglia versus myeloid cell nomenclature during brain inflammation. Front. Immunol. 6, 249–249 (2015).
Perry, V. H. & Gordon, S. Macrophages and microglia in the nervous system. Trends Neurosci. 11, 273–277 (1988).
Davalos, D. et al. ATP mediates rapid microglial response to local brain injury in vivo. Nat. Neurosci. 8, 752–758 (2005). Together with reference 49, these studies were the first to demonstrate the dynamic nature of microglial processes at steady state and in response to injury.
Nimmerjahn, A., Kirchhoff, F. & Helmchen, F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 1314–1318 (2005).
Jansen, I. E. et al. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk. Nat. Genet. 51, 404–413 (2019).
Villegas-Llerena, C., Phillips, A., Garcia-Reitboeck, P., Hardy, J. & Pocock, J. M. Microglial genes regulating neuroinflammation in the progression of Alzheimer’s disease. Curr. Opin. Neurobiol. 36, 74–81 (2016).
Schafer, D. P. et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74, 691–705 (2012). Together with reference 53, this study demonstrated the role of complement molecules in synapse elimination by microglia during development.
Stevens, B. et al. The classical complement cascade mediates CNS synapse elimination. Cell 131, 1164–1178 (2007).
Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010). This study used elegant fate mapping approaches to demonstrate the embryonic origin of microglia.
Schulz, C. et al. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336, 86–90 (2012).
Mass, E. et al. A somatic mutation in erythro-myeloid progenitors causes neurodegenerative disease. Nature 549, 389–393 (2017). This work showed that somatic mutations specifically in embryonic progenitors of microglia can cause neuronal loss, likely explaining why some patients with histiocytosis develop neurodegenerative disease.
Kreutzberg, G. W. Microglia: a sensor for pathological events in the CNS. Trends Neurosci. 19, 312–318 (1996).
Beccari, S., Diaz-Aparicio, I. & Sierra, A. Quantifying microglial phagocytosis of apoptotic cells in the brain in health and disease. Curr. Protoc. Immunol. 122, e49 (2018).
Korin, B. et al. High-dimensional, single-cell characterization of the brain’s immune compartment. Nat. Neurosci. 20, 1300–1309 (2017).
Da Mesquita, S., Fu, Z. & Kipnis, J. The meningeal lymphatic system: a new player in neurophysiology. Neuron 100, 375–388 (2018).
Kivisäkk, P. et al. Human cerebrospinal fluid central memory CD4+ T cells: evidence for trafficking through choroid plexus and meninges via P-selectin. Proc. Natl Acad. Sci. USA 100, 8389–8394 (2003).
Benakis, C., Llovera, G. & Liesz, A. The meningeal and choroidal infiltration routes for leukocytes in stroke. Ther. Adv. Neurol. Disord. 11, 1756286418783708 (2018).
Radjavi, A., Smirnov, I., Derecki, N. & Kipnis, J. Dynamics of the meningeal CD4+ T-cell repertoire are defined by the cervical lymph nodes and facilitate cognitive task performance in mice. Mol. Psychiatry 19, 531–533 (2014).
Quintana, E. et al. DNGR-1+ dendritic cells are located in meningeal membrane and choroid plexus of the noninjured brain. Glia 63, 2231–2248 (2015).
McCarthy, K. D. & de Vellis, J. Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue. J. Cell Biol. 85, 890–902 (1980).
Sievers, J., Parwaresch, R. & Wottge, H.-U. Blood monocytes and spleen macrophages differentiate into microglia-like cells on monolayers of astrocytes: morphology. Glia 12, 245–258 (1994).
Tanaka, J. & Maeda, N. Microglial ramification requires nondiffusible factors derived from astrocytes. Exp. Neurol. 137, 367–375 (1996).
Bohlen, C. J. et al. Diverse requirements for microglial survival, specification, and function revealed by defined-medium cultures. Neuron 94, 759–773.e8 (2017).
Foo, L. C. et al. Development of a method for the purification and culture of rodent astrocytes. Neuron 71, 799–811 (2011).
Butovsky, O. et al. Identification of a unique TGF-β dependent molecular and functional signature in microglia. Nat. Neurosci. 17, 131–143 (2014). Together with references 110 and 111, this study showed that microglia can be defined by a specific molecular signature in mice.
Greenhalgh, A. D. et al. Peripherally derived macrophages modulate microglial function to reduce inflammation after CNS injury. PLOS Biol. 16, e2005264 (2018).
Gosselin, D. et al. An environment-dependent transcriptional network specifies human microglia identity. Science 356, eaal3222 (2017). This study comprehensively characterized the transcriptional phenotype of human microglia.
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. 215, 1627–1647 (2018). Together with reference 74, this study showed that microglial transcriptomic identity is garnered by both origin and environment.
Bennett, F. C. et al. A combination of ontogeny and CNS environment establishes microglial identity. Neuron 98, 1170–1183 (2018).
Esmonde-White, C. et al. Distinct function-related molecular profile of adult human A2B5-positive pre-oligodendrocytes versus mature oligodendrocytes. J. Neuropathol. Exp. Neurol. 78, 468–479 (2019).
Healy, L. M., Yaqubi, M., Ludwin, S. & Antel, J. P. Species differences in immune-mediated CNS tissue injury and repair: a (neuro)inflammatory topic. Glia https://doi.org/10.1002/glia.23746(2019) (2019).
Même, W. et al. Proinflammatory cytokines released from microglia inhibit gap junctions in astrocytes: potentiation by β-amyloid. FASEB J. 20, 494–496 (2006).
Watanabe, M. et al. Th1 cells downregulate connexin 43 gap junctions in astrocytes via microglial activation. Sci. Rep. 6, 38387 (2016).
Retamal, M. A. et al. Cx43 hemichannels and gap junction channels in astrocytes are regulated oppositely by proinflammatory cytokines released from activated microglia. J. Neurosci. 27, 13781–13792 (2007).
Kirkley, K. S., Popichak, K. A., Afzali, M. F., Legare, M. E. & Tjalkens, R. B. Microglia amplify inflammatory activation of astrocytes in manganese neurotoxicity. J. Neuroinflammation 14, 99 (2017).
Sofroniew, M. V. Astrogliosis. Cold Spring Harb. Perspect. Biol. 7, a020420 (2014).
Hwang, S.-Y. et al. Ionizing radiation induces astrocyte gliosis through microglia activation. Neurobiol. Dis. 21, 457–467 (2006).
Kyrkanides, S., Olschowka, J. A., Williams, J. P., Hansen, J. T. & O’Banion, M. K. TNFα and IL-1β mediate intercellular adhesion molecule-1 induction via microglia-astrocyte interaction in CNS radiation injury. J. Neuroimmunol. 95, 95–106 (1999).
Liddelow, S. A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017).
Anderson, W. D. et al. Computational modeling of cytokine signaling in microglia. Mol. Biosyst. 11, 3332–3346 (2015).
David, S. & Kroner, A. Repertoire of microglial and macrophage responses after spinal cord injury. Nat. Rev. Neurosci. 12, 388–399 (2011).
Schwab, J. M., Zhang, Y., Kopp, M. A., Brommer, B. & Popovich, P. G. The paradox of chronic neuroinflammation, systemic immune suppression, autoimmunity after traumatic chronic spinal cord injury. Exp. Neurol. 258, 121–129 (2014).
Yun, S. P. et al. Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson’s disease. Nat. Med. 24, 931–938 (2018).
Shinozaki, Y. et al. Transformation of astrocytes to a neuroprotective phenotype by microglia via P2Y1 receptor downregulation. Cell Rep. 19, 1151–1164 (2017).
Rothhammer, V. et al. Microglial control of astrocytes in response to microbial metabolites. Nature 557, 724–728 (2018).
Barres, B. A. et al. Cell death and control of cell survival in the oligodendrocyte lineage. Cell 70, 31–46 (1992).
Nicholas, R. S. J., Wing, M. G. & Compston, A. Nonactivated microglia promote oligodendrocyte precursor survival and maturation through the transcription factor NF-κB. Eur. J. Neurosci. 13, 959–967 (2001).
Hagemeyer, N. et al. Microglia contribute to normal myelinogenesis and to oligodendrocyte progenitor maintenance during adulthood. Acta Neuropathol. 134, 441–458 (2017).
Schonberg, D. L. et al. Ferritin stimulates oligodendrocyte genesis in the adult spinal cord and can be transferred from macrophages to NG2 cells in vivo. J. Neurosci. 32, 5374–5384 (2012).
Wlodarczyk, A. et al. A novel microglial subset plays a key role in myelinogenesis in developing brain. EMBO J. 36, 3292–3308 (2017).
Liu, Y. et al. Concentration-dependent effects of CSF1R inhibitors on oligodendrocyte progenitor cells ex vivo and in vivo. Exp. Neurol. 318, 32–41 (2019).
Merrill, J. E., Ignarro, L. J., Sherman, M. P., Melinek, J. & Lane, T. E. Microglial cell cytotoxicity of oligodendrocytes is mediated through nitric oxide. J. Immunol. 151, 2132–2141 (1993).
Zajicek, J., Wing, M., Scolding, N. & Compston, D. Interactions between oligodendrocytes and microglia: a major role for complement and tumour necrosis factor in oligodendrocyte adherence and killing. Brain 115, 1611–1631 (1992).
Moore, C. S. et al. Direct and indirect effects of immune and central nervous system-resident cells on human oligodendrocyte progenitor cell differentiation. J. Immunol. 194, 761–772 (2015).
Miron, V. E. Microglia-driven regulation of oligodendrocyte lineage cells, myelination, and remyelination. J. Leukoc. Biol. 101, 1103–1108 (2017).
Miron, V. E. et al. M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat. Neurosci. 16, 1211–1218 (2013).
Goldmann, T. et al. A new type of microglia gene targeting shows TAK1 to be pivotal in CNS autoimmune inflammation. Nat. Neurosci. 16, 1618–1626 (2013).
Wheeler, N. A. & Fuss, B. Extracellular cues influencing oligodendrocyte differentiation and (re)myelination. Exp. Neurol. 283, 512–530 (2016).
Giera, S. et al. The adhesion G protein-coupled receptor GPR56 is a cell-autonomous regulator of oligodendrocyte development. Nat. Commun. 6, 6121 (2015).
Ackerman, S. D., Garcia, C., Piao, X., Gutmann, D. H. & Monk, K. R. The adhesion GPCR Gpr56 regulates oligodendrocyte development via interactions with Gα12/13 and RhoA. Nat. Commun. 6, 6122 (2015).
Giera, S. et al. Microglial transglutaminase-2 drives myelination and myelin repair via GPR56/ADGRG1 in oligodendrocyte precursor cells. eLife 7, e33385 (2018).
Gibson, E. M. et al. Methotrexate chemotherapy induces persistent tri-glial dysregulation that underlies chemotherapy-related cognitive impairment. Cell 176, 43–55.e13 (2019). This work showed that glial cell dysfunction is the likely cause of methotrexate-induced cognitive impairment.
Engelhardt, B., Vajkoczy, P. & Weller, R. O. The movers and shapers in immune privilege of the CNS. Nat. Immunol. 18, 123–131 (2017).
Ransohoff, R. M. & Brown, M. A. Innate immunity in the central nervous system. J. Clin. Invest. 122, 1164–1171 (2012).
Hickman, S. E. et al. The microglial sensome revealed by direct RNA sequencing. Nat. Neurosci. 16, 1896–1905 (2013).
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).
Ginhoux, F., Lim, S., Hoeffel, G., Low, D. & Huber, T. Origin and differentiation of microglia. Front. Cell. Neurosci. 7, 45 (2013).
Sousa, C. et al. Single-cell transcriptomics reveals distinct inflammation-induced microglia signatures. EMBO Rep. 19, e46171 (2018).
Krasemann, S. et al. The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47, 566–581 (2017). Together with references 216 and 217, this study profiled microglia during development and injury, and introduced the concept of a disease-associated microglial transcriptomic signature.
Butovsky, O. & Weiner, H. L. Microglial signatures and their role in health and disease. Nat. Rev. Neurosci. 19, 622–635 (2018).
Shemer, A. et al. Engrafted parenchymal brain macrophages differ from microglia in transcriptome, chromatin landscape and response to challenge. Nat. Commun. 9, 5206 (2018).
Hines, D. J., Hines, R. M., Mulligan, S. J. & Macvicar, B. A. Microglia processes block the spread of damage in the brain and require functional chloride channels. Glia 57, 1610–1618 (2009).
Szalay, G. et al. Microglia protect against brain injury and their selective elimination dysregulates neuronal network activity after stroke. Nat. Commun. 7, 11499 (2016).
Rice, R. A. et al. Elimination of microglia improves functional outcomes following extensive neuronal loss in the hippocampus. J. Neurosci. 35, 9977–9989 (2015).
Bellver-Landete, V. et al. Microglia are an essential component of the neuroprotective scar that forms after spinal cord injury. Nat. Commun. 10, 518 (2019).
Kigerl, K. A. et al. Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J. Neurosci. 29, 13435–13444 (2009).
Kroner, A. et al. TNF and increased intracellular iron alter macrophage polarization to a detrimental M1 phenotype in the injured spinal cord. Neuron 83, 1098–1116 (2014).
Colonna, M. & Butovsky, O. Microglia function in the central nervous system during health and neurodegeneration. Annu. Rev. Immunol. 35, 441–468 (2017).
Rock, R. B. et al. Role of microglia in central nervous system infections. Clin. Microbiol. Rev. 17, 942–964 (2004).
Neher, J. J. & Cunningham, C. Priming microglia for innate immune memory in the brain. Trends Immunol. 40, 358–374 (2019).
Lee, H.-M., Kang, J., Lee, S. J. & Jo, E.-K. Microglial activation of the NLRP3 inflammasome by the priming signals derived from macrophages infected with mycobacteria. Glia 61, 441–452 (2013).
Qin, Y. et al. Macrophage-microglia networks drive M1 microglia polarization after mycobacterium infection. Inflammation 38, 1609–1616 (2015).
Renner, N. A. et al. Microglia activation by SIV-infected macrophages: alterations in morphology and cytokine secretion. J. Neurovirol. 18, 213–221 (2012).
Wolfe, H., Minogue, A. M., Rooney, S. & Lynch, M. A. Infiltrating macrophages contribute to age-related neuroinflammation in C57/BL6 mice. Mechanisms Ageing Dev. 173, 84–91 (2018).
Shechter, R. & Schwartz, M. Harnessing monocyte-derived macrophages to control central nervous system pathologies: no longer ‘if’ but ‘how’. J. Pathol. 229, 332–346 (2013).
David, S., López-Vales, R. & Wee Yong, V. in Handbook of Clinical Neurology Vol. 109 (eds Verhaagen, J. & McDonald, J. W.) 485–502 (Elsevier, 2012).
Kim, E. & Cho, S. Microglia and monocyte-derived macrophages in stroke. Neurotherapeutics 13, 702–718 (2016).
Hu, X. et al. Microglial and macrophage polarization — new prospects for brain repair. Nat. Rev. Neurol. 11, 56–64 (2015).
McKee, C. A. & Lukens, J. R. Emerging roles for the immune system in traumatic brain injury. Front. Immunol. 7, 556–556 (2016).
Ge, R. et al. Choroid plexus-cerebrospinal fluid route for monocyte-derived macrophages after stroke. J. Neuroinflammation 14, 153 (2017).
Shechter, R. et al. Recruitment of beneficial M2 macrophages to injured spinal cord is orchestrated by remote brain choroid plexus. Immunity 38, 555–569 (2013).
Kertser, A. et al. IFN-γ-dependent activation of the brain’s choroid plexus for CNS immune surveillance and repair. Brain 136, 3427–3440 (2013).
Kunis, G., Baruch, K., Miller, O. & Schwartz, M. Immunization with a myelin-derived antigen activates the Brain’s choroid plexus for recruitment of immunoregulatory cells to the CNS and attenuates disease progression in a mouse model of ALS. J. Neurosci. 35, 6381–6393 (2015).
Szmydynger-Chodobska, J. et al. Posttraumatic invasion of monocytes across the blood—cerebrospinal fluid barrier. J. Cereb. Blood Flow Metab. 32, 93–104 (2012).
Zarruk, J. G., Greenhalgh, A. D. & David, S. Microglia and macrophages differ in their inflammatory profile after permanent brain ischemia. Exp. Neurol. 301, 120–132 (2018).
Greenhalgh, A. D. & David, S. Differences in the phagocytic response of microglia and peripheral macrophages after spinal cord injury and its effects on cell death. J. Neurosci. 34, 6316–6322 (2014).
Ajami, B., Bennett, J. L., Krieger, C., McNagny, K. M. & Rossi, F. M. V. Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nat. Neurosci. 14, 1142–1149 (2011).
Baruch, K. et al. PD-1 immune checkpoint blockade reduces pathology and improves memory in mouse models of Alzheimer’s disease. Nat. Med. 22, 135–137 (2016).
Prinz, M. & Priller, J. The role of peripheral immune cells in the CNS in steady state and disease. Nat. Neurosci. 20, 136–144 (2017).
Guillot-Sestier, M.-V. et al. IL10 deficiency rebalances innate immunity to mitigate Alzheimer-like pathology. Neuron 85, 534–548 (2015).
Koronyo, Y. et al. Therapeutic effects of glatiramer acetate and grafted CD115+ monocytes in a mouse model of Alzheimer’s disease. Brain 138, 2399–2422 (2015).
Wang, Y. et al. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J. Exp. Med. 213, 667–675 (2016).
Fekete, R. et al. Microglia control the spread of neurotropic virus infection via P2Y12 signalling and recruit monocytes through P2Y12-independent mechanisms. Acta Neuropathol. 136, 461–482 (2018).
Grønberg, N. V., Johansen, F. F., Kristiansen, U. & Hasseldam, H. Leukocyte infiltration in experimental stroke. J. Neuroinflammation 10, 115 (2013).
Taylor, R. A. et al. TGF-β1 modulates microglial phenotype and promotes recovery after intracerebral hemorrhage. J. Clin. Invest. 127, 280–292 (2017).
Yamasaki, R. et al. Differential roles of microglia and monocytes in the inflamed central nervous system. J. Exp. Med. 211, 1533–1549 (2014).
Anderson, W. D., Greenhalgh, A. D., Takwale, A., David, S. & Vadigepalli, R. Novel influences of IL-10 on CNS inflammation revealed by integrated analyses of cytokine networks and microglial morphology. Front. Cell. Neurosci. 11, 233 (2017).
Sharma, S. et al. Bone marrow mononuclear cells protect neurons and modulate microglia in cell culture models of ischemic stroke. J. Neurosci. Res. 88, 2869–2876 (2010).
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).
Frik, J. et al. Cross-talk between monocyte invasion and astrocyte proliferation regulates scarring in brain injury. EMBO Rep. 19, e45294 (2018).
Haan, N., Zhu, B., Wang, J., Wei, X. & Song, B. Crosstalk between macrophages and astrocytes affects proliferation, reactive phenotype and inflammatory response, suggesting a role during reactive gliosis following spinal cord injury. J. Neuroinflammation 12, 109 (2015).
Andjelkovic, A. V., Kerkovich, D. & Pachter, J. S. Monocyte:astrocyte interactions regulate MCP-1 expression in both cell types. J. Leukoc. Biol. 68, 545–552 (2000).
Harris, J. E. et al. Monocyte-astrocyte networks regulate matrix metalloproteinase gene expression and secretion in central nervous system tuberculosis in vitro and in vivo. J. Immunol. 178, 1199–1207 (2007).
Kurimoto, T. et al. Neutrophils express oncomodulin and promote optic nerve regeneration. J. Neurosci. 33, 14816–14824 (2013).
Zenaro, E. et al. Neutrophils promote Alzheimer’s disease-like pathology and cognitive decline via LFA-1 integrin. Nat. Med. 21, 880–886 (2015).
Schwab, J. M., Chiang, N., Arita, M. & Serhan, C. N. Resolvin E1 and protectin D1 activate inflammation-resolution programmes. Nature 447, 869–874 (2007).
Davies, C. L., Patir, A. & McColl, B. W. Myeloid cell and transcriptome signatures associated with inflammation resolution in a model of self-limiting acute brain inflammation. Front. Immunol. 10, 1048 (2019).
Serhan, C. N., Dalli, J., Colas, R. A., Winkler, J. W. & Chiang, N. Protectins and maresins: New pro-resolving families of mediators in acute inflammation and resolution bioactive metabolome. Biochim. Biophys. Acta 1851, 397–413 (2015).
Francos-Quijorna, I. et al. Maresin 1 promotes inflammatory resolution, neuroprotection, and functional neurological recovery after spinal cord injury. J. Neurosci. 37, 11731–11743 (2017).
Neumann, J. et al. Beware the intruder: real time observation of infiltrated neutrophils and neutrophil–microglia interaction during stroke in vivo. PLOS ONE 13, e0193970 (2018).
Gordon, S. Alternative activation of macrophages. Nat. Rev. Immunol. 3, 23–35 (2003).
Powell, D., Lou, M., Barros Becker, F. & Huttenlocher, A. Cxcr1 mediates recruitment of neutrophils and supports proliferation of tumor-initiating astrocytes in vivo. Sci. Rep. 8, 13285 (2018).
Hooshmand, M. J. et al. Neutrophils induce astroglial differentiation and migration of human neural stem cells via C1q and C3a synthesis. J. Immunol. 199, 1069–1085 (2017).
Ng, L. G., Ostuni, R. & Hidalgo, A. Heterogeneity of neutrophils. Nat. Rev. Immunol. 19, 255–265 (2019).
Filiano, A. J. et al. Unexpected role of interferon-γ in regulating neuronal connectivity and social behaviour. Nature 535, 425–429 (2016).
Derecki, N. C. et al. Regulation of learning and memory by meningeal immunity: a key role for IL-4. J. Exp. Med. 207, 1067–1080 (2010).
Murray, P. J. et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41, 14–20 (2014).
Filippi, M. et al. Multiple sclerosis. Nat. Rev. Dis. Primers 4, 43 (2018).
Dobson, R. & Giovannoni, G. Multiple sclerosis – a review. Eur. J. Neurol. 26, 27–40 (2019).
Li, R., Patterson, K. R. & Bar-Or, A. Reassessing B cell contributions in multiple sclerosis. Nat. Immunol. 19, 696–707 (2018).
Brennan, F. H. & Popovich, P. G. Emerging targets for reprograming the immune response to promote repair and recovery of function after spinal cord injury. Curr. Opin. Neurol. 31, 334–344 (2018).
Raposo, C. et al. CNS repair requires both effector and regulatory T cells with distinct temporal and spatial profiles. J. Neurosci. 34, 10141–10155 (2014).
Vindegaard, N. et al. T-cells and macrophages peak weeks after experimental stroke: spatial and temporal characteristics. Neuropathology 37, 407–414 (2017).
Cramer, J. V., Benakis, C. & Liesz, A. T cells in the post-ischemic brain: troopers or paramedics? J. Neuroimmunol. 326, 33–37 (2019).
Zrzavy, T. et al. Dominant role of microglial and macrophage innate immune responses in human ischemic infarcts. Brain Pathol. 28, 791–805 (2018).
Fleming, J. C. et al. The cellular inflammatory response in human spinal cords after injury. Brain 129, 3249–3269 (2006).
Ito, M. et al. Brain regulatory T cells suppress astrogliosis and potentiate neurological recovery. Nature 565, 246–250 (2019).
Unger, M. S. et al. Doublecortin expression in CD8+ T-cells and microglia at sites of amyloid-β plaques: a potential role in shaping plaque pathology? Alzheimers Dement. 14, 1022–1037 (2018).
Merlini, M., Kirabali, T., Kulic, L., Nitsch, R. M. & Ferretti, M. T. Extravascular CD3+ T cells in brains of Alzheimer disease patients correlate with tau but not with amyloid pathology: an immunohistochemical study. Neurodegener. Dis. 18, 49–56 (2018).
Togo, T. et al. Occurrence of T cells in the brain of Alzheimer’s disease and other neurological diseases. J. Neuroimmunol. 124, 83–92 (2002).
Brochard, V. et al. Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J. Clin. Invest. 119, 182–192 (2009).
Troost, D., van den Oord, J. J. & Vianney de Jong, J. M. Immunohistochemical characterization of the inflammatory infiltrate in amyotrophic lateral sclerosis. Neuropathol. Appl. Neurobiol. 16, 401–410 (1990).
Engelhardt, J. I., Tajti, J. & Appel, S. H. Lymphocytic infiltrates in the spinal cord in amyotrophic lateral sclerosis. Arch. Neurol. 50, 30–36 (1993).
Beers, D. R. & Appel, S. H. Immune dysregulation in amyotrophic lateral sclerosis: mechanisms and emerging therapies. Lancet Neurol. 18, 211–220 (2019).
González, H., Contreras, F. & Pacheco, R. Regulation of the neurodegenerative process associated to Parkinson’s disease by CD4+ T-cells. J. Neuroimmune Pharmacol. 10, 561–575 (2015).
van Dyck, C. H. Anti-amyloid-β monoclonal antibodies for Alzheimer’s disease: pitfalls and promise. Biol. Psychiatry 83, 311–319 (2018).
Bachmann, M. F., Jennings, G. T. & Vogel, M. A vaccine against Alzheimer’s disease: anything left but faith? Expert Opin. Biol. Ther. 19, 73–78 (2019).
Bodhankar, S., Chen, Y., Vandenbark, A. A., Murphy, S. J. & Offner, H. Treatment of experimental stroke with IL-10-producing B-cells reduces infarct size and peripheral and CNS inflammation in wild-type B-cell-sufficient mice. Metab. Brain Dis. 29, 59–73 (2014).
Ankeny, D. P., Guan, Z. & Popovich, P. G. B cells produce pathogenic antibodies and impair recovery after spinal cord injury in mice. J. Clin. Invest. 119, 2990–2999 (2009).
Doyle, K. P. et al. B-lymphocyte-mediated delayed cognitive impairment following stroke. J. Neurosci. 35, 2133–2145 (2015).
Westendorp, W. F., Nederkoorn, P. J., Vermeij, J. D., Dijkgraaf, M. G. & de Beek, D. V. Post-stroke infection: a systematic review and meta-analysis. BMC Neurol. 11, 110 (2011).
Sun, G. et al. γδ T cells provide the early source of IFN-γ to aggravate lesions in spinal cord injury. J. Exp. Med. 215, 521–535 (2018).
Liesz, A. et al. Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat. Med. 15, 192–199 (2009). This was one of the first studies to show a protective role of T reg cells in experimental stroke.
Na, S.-Y., Mracsko, E., Liesz, A., Hünig, T. & Veltkamp, R. Amplification of regulatory T cells using a CD28 superagonist reduces brain damage after ischemic stroke in mice. Stroke 46, 212–220 (2015).
Xie, L. et al. mTOR signaling inhibition modulates macrophage/microglia-mediated neuroinflammation and secondary injury via regulatory T cells after focal ischemia. J. Immunol. 192, 6009–6019 (2014).
Xie, L., Choudhury, G. R., Winters, A., Yang, S. H. & Jin, K. Cerebral regulatory T cells restrain microglia/macrophage-mediated inflammatory responses via IL-10. Eur. J. Immunol 45, 180–191 (2015).
Wu, B. et al. Improved regeneration after spinal cord injury in mice lacking functional T- and B-lymphocytes. Exp. Neurol. 237, 274–285 (2012).
Späni, C. et al. Reduced β-amyloid pathology in an APP transgenic mouse model of Alzheimer’s disease lacking functional B and T cells. Acta Neuropathol. Commun. 3, 71 (2015).
Browne, T. C. et al. IFN-γ production by amyloid β-specific Th1 cells promotes microglial activation and increases plaque burden in a mouse model of Alzheimer’s disease. J. Immunol. 190, 2241–2251 (2013).
Marsh, S. E. et al. The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function. Proc. Natl Acad. Sci. USA 113, E1316–E1325 (2016).
Pasinelli, P. & Brown, R. H. Molecular biology of amyotrophic lateral sclerosis: insights from genetics. Nat. Rev. Neurosci. 7, 710–723 (2006).
McGeer, P. L. & McGeer, E. G. Inflammatory processes in amyotrophic lateral sclerosis. Muscle Nerve 26, 459–470 (2002).
Chiu, I. M. et al. T lymphocytes potentiate endogenous neuroprotective inflammation in a mouse model of ALS. Proc. Natl Acad. Sci. USA 105, 17913–17918 (2008).
Sheean, R. K. et al. Association of regulatory T-cell expansion with progression of amyotrophic lateral sclerosis: a study of humans and a transgenic mouse model. JAMA Neurol. 75, 681–689 (2018).
Korhonen, P. et al. Long-term interleukin-33 treatment delays disease onset and alleviates astrocytic activation in a transgenic mouse model of amyotrophic lateral sclerosis. IBRO Rep. 6, 74–86 (2019).
Gadani, S. P. et al. The glia-derived alarmin IL-33 orchestrates the immune response and promotes recovery following CNS injury. Neuron 85, 703–709 (2015).
Harms, A. S. et al. MHCII is required for α-synuclein-induced activation of microglia, CD4 T cell proliferation, and dopaminergic neurodegeneration. J. Neurosci. 33, 9592–9600 (2013).
Sommer, A. et al. Infiltrating T lymphocytes reduce myeloid phagocytosis activity in synucleinopathy model. J. Neuroinflammation 13, 174 (2016).
Fan, K.-Q. et al. Stress-induced metabolic disorder in peripheral CD4+ T cells leads to anxiety-like behavior. Cell 179, 864–879 (2019). This study showed that T cell-mediated actions on oligodendrocytes in a specific brain region affect behaviour.
Ransohoff, R. M. A polarizing question: do M1 and M2 microglia exist? Nat. Neurosci. 19, 987–991 (2016).
Hammond, T. R. et al. Single-cell RNA sequencing of microglia throughout the mouse lifespan and in the injured brain reveals complex cell-state changes. Immunity 50, 253–271 (2019).
Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290 (2017).
O’Koren, E. G. et al. Microglial function is distinct in different anatomical locations during retinal homeostasis and degeneration. Immunity 50, 723–737.e7 (2019).
Rothhammer, V. et al. Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat. Med. 22, 586–597 (2016).
Park, J. et al. A 3D human triculture system modeling neurodegeneration and neuroinflammation in Alzheimer’s disease. Nat. Neurosci. 21, 941–951 (2018).
Ormel, P. R. et al. Microglia innately develop within cerebral organoids. Nat. Commun. 9, 4167 (2018).
Li, Q. et al. Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing. Neuron 101, 207–223 (2019).
Cohen, M. et al. Lung single-cell signaling interaction map reveals basophil role in macrophage imprinting. Cell 175, 1031–1044 (2018).
Guttenplan, K. A. & Liddelow, S. A. Astrocytes and microglia: models and tools. J. Exp. Med. 216, 71–83 (2019).
Bohlen, C. J., Bennett, F. C. & Bennett, M. L. Isolation and culture of microglia. Curr. Protoc. Immunol. 125, e70 (2019).
Qian, X., Song, H. & Ming, G. L. Brain organoids: advances, applications and challenges. Development 146, dev166074 (2019).
Marton, R. M. et al. Differentiation and maturation of oligodendrocytes in human three-dimensional neural cultures. Nat. Neurosci. 22, 484–491 (2019).
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).
Buttgereit, A. et al. Sall1 is a transcriptional regulator defining microglia identity and function. Nat. Immunol. 17, 1397–1406 (2016).
Haimon, Z. et al. Re-evaluating microglia expression profiles using RiboTag and cell isolation strategies. Nat. Immunol. 19, 636–644 (2018).
van den Brink, S. C. et al. Single-cell sequencing reveals dissociation-induced gene expression in tissue subpopulations. Nat. Methods 14, 935–936 (2017).
Bonnardel, J. et al. Stellate cells, hepatocytes, and endothelial cells imprint the Kupffer cell identity on monocytes colonizing the liver macrophage niche. Immunity 51, 638–654 (2019).
Srinivasan, R. et al. New transgenic mouse lines for selectively targeting astrocytes and studying calcium signals in astrocyte processes in situ and in vivo. Neuron 92, 1181–1195 (2016).
Sun, L. O. et al. Spatiotemporal control of CNS myelination by oligodendrocyte programmed cell death through the TFEB-PUMA axis. Cell 175, 1811–1826 (2018).
von Jonquieres, G. et al. Glial promoter selectivity following AAV-delivery to the immature brain. PLOS ONE 8, e65646 (2013).
Varvel, N. H. et al. Microglial repopulation model reveals a robust homeostatic process for replacing CNS myeloid cells. Proc. Natl Acad. Sci. USA 109, 18150–18155 (2012).
Heppner, F. L. et al. Experimental autoimmune encephalomyelitis repressed by microglial paralysis. Nat. Med. 11, 146–152 (2005).
Kitic, M., See, P., Bruttger, J., Ginhoux, F. & Waisman, A. in Microglia: Methods and Protocols (eds Garaschuk, O. & Verkhratsky, A.) 217–230 (Springer, 2019).
Elmore, M. R. P. 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 was the first study to use a CSF1R antagonist to ablate microglia from the adult mouse brain.
Han, J., Harris, R. A. & Zhang, X.-M. An updated assessment of microglia depletion: current concepts and future directions. Mol. Brain 10, 25 (2017).
Rojo, R. et al. Deletion of a Csf1r enhancer selectively impacts CSF1R expression and development of tissue macrophage populations. Nat. Commun. 10, 3215 (2019).
The Jackson Laboratory. Immunodeficient mouse and xenograft host comparisons. Jackson Lab. https://www.jax.org/jax-mice-and-services/find-and-order-jax-mice/most-popular-jax-mice-strains/immunodeficient-mouse-and-xenograft-host-comparisons (2019).
Herz, J. et al. Role of neutrophils in exacerbation of brain injury after focal cerebral ischemia in hyperlipidemic mice. Stroke 46, 2916–2925 (2015).
The authors thank the all the scientists involved in producing the original work and we hope we have done justice to their findings.
The authors declare no competing interests.
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Phagocytic immune cells involved in homeostasis and inflammation. They may be tissue resident or recruited from circulating monocyte populations to sites of inflammation.
- Genome-wide association studies
Studies that integrate whole genomes across populations to identify genetic variants in individuals and associate those variants with a trait.
- Lymphatic system
A vascular network that drains fluid from the extracellular space and traffics this and immune cells to lymphoid organs and the systemic circulation.
- Adaptive immune cell
A T cell or B cell that can acquire and maintain specific knowledge of non-self-pathogens (or self-antigens during disease) to mount a specific immune response.
Innate immune cells that are often the first recruits to sites of inflammation, where they release antimicrobial agents, enzymes, nitrogen oxides and other proteins.
Cells that develop in the bone marrow, are released into the circulation and can be recruited during inflammation. Monocytes give rise to monocyte-derived cells such as macrophages (but are often functionally distinct from tissue-resident macrophage populations).
- Dendritic cells
Antigen-presenting cells that exert immune surveillance for exogenous and endogenous antigens for the activation of naive T cells giving rise to various immunological responses.
- Innate lymphoid cells
Immune cells that belong to the lymphoid lineage but do not express antigen-specific receptors and are therefore involved in innate immune regulation of homeostasis and inflammation.
A cell that is derived from a haematopoietic stem cell. Lymphocytes ultimately form the cells of the adaptive immune system.
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Greenhalgh, A.D., David, S. & Bennett, F.C. Immune cell regulation of glia during CNS injury and disease. Nat Rev Neurosci 21, 139–152 (2020). https://doi.org/10.1038/s41583-020-0263-9
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