Microglial cell origin and phenotypes in health and disease

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

Ransohoff, R. M. & Perry, V. H. Microglial physiology: unique stimuli, specialized responses. Annu. Rev. Immunol. 27, 119–145 (2009).

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).

Perry, V. H. & Gordon, S. Macrophages and the nervous system. Int. Rev. Cytol. 125, 203–244 (1991).

Glass, C. K., Saijo, K., Winner, B., Marchetto, M. C. & Gage, F. H. Mechanisms underlying inflammation in neurodegeneration. Cell 140, 918–934 (2010).

Perry, V. H., Nicoll, J. A. & Holmes, C. Microglia in neurodegenerative disease. Nature Rev. Neurol. 6, 193–201 (2010).

Rio-Hortega, P. D. in Cytology and Cellular Pathology of the Nervous System (ed. Penfield, W.) 482–534 (P.B. Hoeber, Inc., New York, 1932).

MacDonald, K. P. et al. An antibody against the colony-stimulating factor 1 receptor depletes the resident subset of monocytes and tissue- and tumor-associated macrophages but does not inhibit inflammation. Blood 116, 3955–3963 (2010).

Beers, D. R. et al. Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis. Proc. Natl Acad. Sci. USA 103, 16021–16026 (2006).

Eglitis, M. A. & Mezey, E. Hematopoietic cells differentiate into both microglia and macroglia in the brains of adult mice. Proc. Natl Acad. Sci. USA 94, 4080–4085 (1997).

Priller, J. et al. Targeting gene-modified hematopoietic cells to the central nervous system: use of green fluorescent protein uncovers microglial engraftment. Nature Med. 7, 1356–1361 (2001).

Hickey, W. F. & Kimura, H. Perivascular microglial cells of the CNS are bone marrow-derived and present antigen in vivo. Science 239, 290–292 (1988).

Ransohoff, R. M. Microgliosis: the questions shape the answers. Nature Neurosci. 10, 1507–1509 (2007).

Tanaka, R. et al. Migration of enhanced green fluorescent protein expressing bone marrow-derived microglia/macrophage into the mouse brain following permanent focal ischemia. Neuroscience 117, 531–539 (2003).

Mildner, A. et al. Distinct and non-redundant roles of microglia and myeloid subsets in mouse models of Alzheimer's disease. J. Neurosci. 31, 11159–11171 (2011).

Ajami, B., Bennett, J. L., Krieger, C., Tetzlaff, W. & Rossi, F. M. Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nature Neurosci. 10, 1538–1543 (2007).

Mildner, A. et al. Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions. Nature Neurosci. 10, 1544–1553 (2007).

Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010). This study provides evidence that brain parenchymal microglia are derived from primitive yolk sac macrophages and are distinct from HSC-derived macrophages.

Samokhvalov, I. M., Samokhvalova, N. I. & Nishikawa, S. Cell tracing shows the contribution of the yolk sac to adult haematopoiesis. Nature 446, 1056–1061 (2007).

King, I. L., Dickendesher, T. L. & Segal, B. M. Circulating Ly-6C+ myeloid precursors migrate to the CNS and play a pathogenic role during autoimmune demyelinating disease. Blood 113, 3190–3197 (2009).

Mildner, A. et al. CCR2+Ly-6Chi monocytes are crucial for the effector phase of autoimmunity in the central nervous system. Brain 132, 2487–2500 (2009).

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. Nature Neurosci. 14, 1142–1149 (2011). This study identified distinct roles for infiltrating monocytes and resident microglia in neuroinflammation and progression of EAE.

Fellner, L., Jellinger, K. A., Wenning, G. K. & Stefanova, N. Glial dysfunction in the pathogenesis of α-synucleinopathies: emerging concepts. Acta Neuropathol. 121, 675–693 (2011).

Reitz, C., Brayne, C. & Mayeux, R. Epidemiology of Alzheimer disease. Nature Rev. Neurol. 7, 137–152 (2011).

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

Chorro, L. et al. Langerhans cell (LC) proliferation mediates neonatal development, homeostasis, and inflammation-associated expansion of the epidermal LC network. J. Exp. Med. 206, 3089–3100 (2009).

Polazzi, E. & Monti, B. Microglia and neuroprotection: from in vitro studies to therapeutic applications. Prog. Neurobiol. 92, 293–315 (2010).

Dimos, J. T. et al. Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 321, 1218–1221 (2008).

Park, I. H. et al. Disease-specific induced pluripotent stem cells. Cell 134, 877–886 (2008).

Soldner, F. et al. Generation of isogenic pluripotent stem cells differing exclusively at two early onset parkinson point mutations. Cell 416, 318–331 (2011).

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

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).

de Haas, A. H., Boddeke, H. W. & Biber, K. Region-specific expression of immunoregulatory proteins on microglia in the healthy CNS. Glia 56, 888–894 (2008).

Martinez, F. O., Helming, L. & Gordon, S. Alternative activation of macrophages: an immunologic functional perspective. Annu. Rev. Immunol. 27, 451–483 (2009).

Odegaard, J. I. & Chawla, A. Alternative macrophage activation and metabolism. Annu. Rev. Pathol. 6, 275–297 (2011).

Olefsky, J. M. & Glass, C. K. Macrophages, inflammation, and insulin resistance. Annu. Rev. Physiol. 72, 219–246 (2010).

Sica, A. et al. Macrophage polarization in tumour progression. Semin. Cancer Biol. 18, 349–355 (2008).

Nimmerjahn, A., Kirchhoff, F. & Helmchen, F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 1314–1318 (2005).

Bessis, A., Bechade, C., Bernard, D. & Roumier, A. Microglial control of neuronal death and synaptic properties. Glia 55, 233–238 (2007).

Paolicelli, R. C. et al. Synaptic pruning by microglia is necessary for normal brain development. Science 333, 1456–1458 (2011). This study showed that microglia actively engulf synaptic material and have a major role in synaptic pruning during postnatal development in mice.

Sierra, A. et al. Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell 7, 483–495 (2010). This study reported a role for microglia in supporting adult neurogenesis through phagocytosis of apoptotic neuroprogenitor cells in the subgranular zone niche of the hippocampus.

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

Fuhrmann, M. et al. Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer's disease. Nature Neurosci. 13, 411–413 (2010).

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

Turnbull, I. R. et al. Cutting edge: TREM-2 attenuates macrophage activation. J. Immunol. 177, 3520–3524 (2006).

Hamerman, J. A. et al. Cutting edge: inhibition of TLR and FcR responses in macrophages by triggering receptor expressed on myeloid cells (TREM)-2 and DAP12. J. Immunol. 177, 2051–2055 (2006).

Paloneva, J. et al. Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. Am. J. Hum. Genet. 71, 656–662 (2002).

Chen, G. Y. & Nunez, G. Sterile inflammation: sensing and reacting to damage. Nature Rev. Immunol. 10, 826–837 (2010).

Grivennikov, S. I., Greten, F. R. & Karin, M. Immunity, inflammation, and cancer. Cell 140, 883–899 (2010).

Qian, B. Z. & Pollard, J. W. Macrophage diversity enhances tumor progression and metastasis. Cell 141, 39–51 (2010).

Penfield, W. Microglia and the process of phagocytosis in gliomas. Am. J. Pathol. 1, 77–90. 15 (1925).

Charles, N. A., Holland, E. C., Gilbertson, R., Glass, R. & Kettenmann, H. The brain tumor microenvironment. Glia 59, 1169–1180 (2011).

Ghosh, A. & Chaudhuri, S. Microglial action in glioma: a boon turns bane. Immunol. Lett. 131, 3–9 (2010).

Qiu, B. et al. IL-10 and TGF-β2 are overexpressed in tumor spheres cultured from human gliomas. Mol. Biol. Rep. 38, 3585–3591 (2011).

Wu, A. et al. Glioma cancer stem cells induce immunosuppressive macrophages/microglia. Neuro Oncol. 12, 1113–1125 (2010).

Black, K. L., Chen, K., Becker, D. P. & Merrill, J. E. Inflammatory leukocytes associated with increased immunosuppression by glioblastoma. J. Neurosurg. 77, 120–126 (1992).

Wei, J. et al. Glioma-associated cancer-initiating cells induce immunosuppression. Clin. Cancer Res. 16, 461–473 (2010).

Zou, J. P. et al. Human glioma-induced immunosuppression involves soluble factor(s) that alters monocyte cytokine profile and surface markers. J. Immunol. 162, 4882–4892 (1999).

Gabrilovich, D. I. & Nagaraj, S. Myeloid-derived suppressor cells as regulators of the immune system. Nature Rev. Immunol. 9, 162–174 (2009).

Ostrand-Rosenberg, S. & Sinha, P. Myeloid-derived suppressor cells: linking inflammation and cancer. J. Immunol. 182, 4499–4506 (2009).

Yang, I., Han, S. J., Kaur, G., Crane, C. & Parsa, A. T. The role of microglia in central nervous system immunity and glioma immunology. J. Clin. Neurosci. 17, 6–10 (2010).

Markovic, D. S., Glass, R., Synowitz, M., Rooijen, N. & Kettenmann, H. Microglia stimulate the invasiveness of glioma cells by increasing the activity of metalloprotease-2. J. Neuropathol. Exp. Neurol. 64, 754–762 (2005).

Markovic, D. S. et al. Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion. Proc. Natl Acad. Sci. USA 106, 12530–12535 (2009). This study showed that MMP14 is upregulated in glioma-associated microglia, and that microglial MMP14 promotes glioma expansion through activation of glioma-derived pro-MMP2.

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

O'Keefe, G. M., Nguyen, V. T. & Benveniste, E. N. Regulation and function of class II major histocompatibility complex, CD40, and B7 expression in macrophages and microglia: implications in neurological diseases. J. Neurovirol. 8, 496–512 (2002).

Saijo, K. et al. A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death. Cell 137, 47–59 (2009). This study defined an anti-inflammatory function of the orphan nuclear receptor NURR1 in microglia and astrocytes and demonstrated how inflammatory signals initiated by microglia can be amplified by astrocytes to promote neurotoxicity.

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

Bauman, D. R. et al. 25-Hydroxycholesterol secreted by macrophages in response to Toll-like receptor activation suppresses immunoglobulin A production. Proc. Natl Acad. Sci. USA 106, 16764–16769 (2009).

Wang, H. et al. HMG-1 as a late mediator of endotoxin lethality in mice. Science 285, 248–251 (1999).

Xu, J. et al. Extracellular histones are major mediators of death in sepsis. Nature Med. 15, 1318–1321 (2009).

Burguillos, M. A. et al. Caspase signalling controls microglia activation and neurotoxicity. Nature 472, 319–324 (2011). This study demonstrates that caspase 8, caspase 3 and caspase 7 regulate microglia activation, and suggests that microglia-specific inhibition of these caspases could be neuroprotective.

Halle, A. et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-β. Nature Immunol. 9, 857–865 (2008).

Salminen, A., Ojala, J., Suuronen, T., Kaarniranta, K. & Kauppinen, A. Amyloid-β oligomers set fire to inflammasomes and induce Alzheimer's pathology. J. Cell. Mol. Med. 12, 2255–2262 (2008).

Sims, G. P., Rowe, D. C., Rietdijk, S. T., Herbst, R. & Coyle, A. J. HMGB1 and RAGE in inflammation and cancer. Annu. Rev. Immunol. 28, 367–388 (2010).

Inoue, K. Purinergic systems in microglia. Cell. Mol. Life Sci. 65, 3074–3080 (2008).

Junger, W. G. Immune cell regulation by autocrine purinergic signalling. Nature Rev. Immunol. 11, 201–212 (2011).

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

Volonté, C., Apolloni, S., Carri, M. T. & D'Ambrosi, N. ALS: focus on purinergic signalling. Pharmacol. Ther. 132, 111–122 (2011).

Erlandsson Harris, H. & Andersson, U. Mini-review: The nuclear protein HMGB1 as a proinflammatory mediator. Eur. J. Immunol. 34, 1503–1512 (2004).

Yan, S. D., Bierhaus, A., Nawroth, P. P. & Stern, D. M. RAGE and Alzheimer's disease: a progression factor for amyloid-β-induced cellular perturbation? J. Alzheimers Dis. 16, 833–843 (2009).

Hansson, G. K. & Hermansson, A. The immune system in atherosclerosis. Nature Immunol. 12, 204–212 (2011).

Goldfine, A. B., Fonseca, V. & Shoelson, S. E. Therapeutic approaches to target inflammation in type 2 diabetes. Clin. Chem. 57, 162–167 (2011).

Saijo, K., Crotti, A. & Glass, C. K. Nuclear receptors, inflammation, and neurodegenerative diseases. Adv. Immunol. 106, 21–59 (2010).

Braak, H. et al. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol. Aging 24, 197–211 (2003).

Hirsch, E. C. & Hunot, S. Neuroinflammation in Parkinson's disease: a target for neuroprotection? Lancet Neurol. 8, 382–397 (2009).

Dutta, G., Zhang, P. & Liu, B. The lipopolysaccharide Parkinson's disease animal model: mechanistic studies and drug discovery. Fundam. Clin. Pharmacol. 22, 453–464 (2008).

Roodveldt, C., Christodoulou, J. & Dobson, C. M. Immunological features of α-synuclein in Parkinson's disease. J. Cell. Mol. Med. 12, 1820–1829 (2008).

Landreth, G. E. & Reed-Geaghan, E. G. Toll-like receptors in Alzheimer's disease. Curr. Top. Microbiol. Immunol. 336, 137–153 (2009).

Daborg, J. et al. Association of the RAGE G82S polymorphism with Alzheimer's disease. J. Neural Transm. 117, 861–867 (2010).

Li, K. et al. Association between the RAGE G82S polymorphism and Alzheimer's disease. J. Neural Transm. 117, 97–104 (2010).

Lee, C. Y. & Landreth, G. E. The role of microglia in amyloid clearance from the AD brain. J. Neural Transm. 117, 949–960 (2010).

Sokolowski, J. D. & Mandell, J. W. Phagocytic clearance in neurodegeneration. Am. J. Pathol. 178, 1416–1428 (2011).

Verghese, P. B., Castellano, J. M. & Holtzman, D. M. Apolipoprotein E in Alzheimer's disease and other neurological disorders. Lancet Neurol. 10, 241–252 (2011).

Kamer, A. R. et al. Inflammation and Alzheimer's disease: possible role of periodontal diseases. Alzheimers Dement. 4, 242–250 (2008).

Finch, C. E. & Morgan, T. E. Systemic inflammation, infection, ApoE alleles, and Alzheimer disease: a position paper. Curr. Alzheimer Res. 4, 185–189 (2007).

Granic, I., Dolga, A. M., Nijholt, I. M., van Dijk, G. & Eisel, U. L. Inflammation and NF-κB in Alzheimer's disease and diabetes. J. Alzheimers Dis. 16, 809–821 (2009).

Jones, A., Kulozik, P., Ostertag, A. & Herzig, S. Common pathological processes and transcriptional pathways in Alzheimer's disease and type 2 diabetes. J. Alzheimers Dis. 16, 787–808 (2009).

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

Lambert, J. C. et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nature Genet. 41, 1094–1099 (2009).

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

Grathwohl, S. A. et al. Formation and maintenance of Alzheimer's disease β-amyloid plaques in the absence of microglia. Nature Neurosci. 12, 1361–1363 (2009). This study demonstrates that CNS amyloid deposits or neurodystrophy are not altered following microglial cell depletion for up to 4 weeks in mouse models of Alzheimer's disease.

Deeks, S. G. HIV infection, inflammation, immunosenescence, and aging. Annu. Rev. Med. 62, 141–155 (2011).

Rackstraw, S. HIV-related neurocognitive impairment — a review. Psychol. Health Med. 16, 548–563 (2011).

Strazza, M., Pirrone, V., Wigdahl, B. & Nonnemacher, M. R. Breaking down the barrier: the effects of HIV-1 on the blood–brain barrier. Brain Res. 1399, 96–115 (2011).

Gannon, P., Khan, M. Z. & Kolson, D. L. Current understanding of HIV-associated neurocognitive disorders pathogenesis. Curr. Opin. Neurol. 24, 275–283 (2011).

Yadav, A. & Collman, R. G. CNS inflammation and macrophage/microglial biology associated with HIV-1 infection. J. Neuroimmune Pharmacol. 4, 430–447 (2009).

Liner, K. J., Ro, M. J. & Robertson, K. R. HIV, antiretroviral therapies, and the brain. Curr. HIV/AIDS Rep. 7, 85–91 (2010).

Hult, B., Chana, G., Masliah, E. & Everall, I. Neurobiology of HIV. Int. Rev. Psychiatry 20, 3–13 (2008).

Saijo, K., Collier, J. G., Li, A. C., Katzenellenbogen, J. A. & Glass, C. K. An ADIOL-ERβ-CtBP transrepression pathway negatively regulates microglia-mediated inflammation. Cell 145, 584–595 (2011). This study identified Δ5-ADIOL as an endogenous inhibitor of microglia activation. Δ5-ADIOL acts through ERβ and suppresses the progession of EAE.

Jellinck, P. H. et al. Dehydroepiandrosterone (DHEA) metabolism in the brain: identification by liquid chromatography/mass spectrometry of the δ-4-isomer of DHEA and related steroids formed from androstenedione by mouse BV2 microglia. J. Steroid Biochem. Mol. Biol. 98, 41–47 (2006).

Kuiper, G. G. et al. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors α and β. Endocrinology 138, 863–870 (1997).

Heiman, M. et al. A translational profiling approach for the molecular characterization of CNS cell types. Cell 135, 738–748 (2008). This study describes a method for quantification of mRNAs undergoing translation in specific neurons within the brain.

Blasius, A. L. & Beutler, B. Intracellular Toll-like receptors. Immunity 32, 305–315 (2010).

Kawai, T. & Akira, S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 34, 637–650 (2011).

Brikos, C. & O'Neill, L. A. Signalling of Toll-like receptors. Handb. Exp. Pharmacol. 183, 21–50 (2008).

Kumar, H., Kawai, T. & Akira, S. Pathogen recognition by the innate immune system. Int. Rev. Immunol. 30, 16–34 (2011).

Barbalat, R., Ewald, S. E., Mouchess, M. L. & Barton, G. M. Nucleic acid recognition by the innate immune system. Annu. Rev. Immunol. 29, 185–214 (2011).

Davis, B. K., Wen, H. & Ting, J. P. The inflammasome NLRs in immunity, inflammation, and associated diseases. Annu. Rev. Immunol. 29, 707–735 (2011).

Schroder, K. & Tschopp, J. The inflammasomes. Cell 140, 821–832 (2010).

Jin, C. & Flavell, R. A. Molecular mechanism of NLRP3 inflammasome activation. J. Clin. Immunol. 30, 628–631 (2010).

Bauernfeind, F. et al. Inflammasomes: current understanding and open questions. Cell. Mol. Life Sci. 68, 765–783 (2011).