Summary
Microglial activation and macrophage infiltration into the CNS are common features of CNS autoimmune disease and of chronic neurodegenerative diseases. Because these cells largely express an overlapping set of common macrophage markers, it has been difficult to separate their respective contributions to disease onset and progression. This problem is further confounded by the many types of macrophages that have been termed microglia. Several approaches, ranging from molecular profiling of isolated cells to the generation of irradiation chimeric rodent models, are now beginning to generate rudimentary definitions distinguishing the various types of microglia and macrophages found within the CNS and the potential roles that these cells may play in health and disease.
Key Words: neuroinflammation, TREM, microglia, Alzheimer’s disease, multiple sclerosis, purinergic receptors, P2Y12
Contributor Information
Monica J. Carson, Email: monica.carson@ucr.edu
Iryna M. Ethell, Email: iryna.ethell@ucr.edu
References
- 1.Rezaie P, Male D. Mesoglia & microglia: a historical review of the concept of mononuclear phagocytes within the central nervous system. J Hist Neurosci. 2002;11:325–374. doi: 10.1076/jhin.11.4.325.8531. [DOI] [PubMed] [Google Scholar]
- 2.Köbbert C, Apps R, Bechmann I, Lanciego JL, Mey J, Thanos S. Current concepts in neuroanatomical tracing. Prog Neurobiol. 2000;62:327–351. doi: 10.1016/S0301-0082(00)00019-8. [DOI] [PubMed] [Google Scholar]
- 3.Carson MJ, Thrash JC, Lo D. Analysis of microglial gene expression: identifying targets for CNS neurodegenerative and autoimmune disease. Am J Pharmacogenomics. 2004;4:321–330. doi: 10.2165/00129785-200404050-00005. [DOI] [PubMed] [Google Scholar]
- 4.Bechmann I. Failed central nervous system regeneration: a downside of immune privilege? Neuromol Med. 2005;7:217–228. doi: 10.1385/NMM:7:3:217. [DOI] [PubMed] [Google Scholar]
- 5.Betmouni S, Perry VH, Gordon JL. Evidence for an early inflammatory response in the central nervous system of mice with scrapie. Neuroscience. 1996;74:1–5. doi: 10.1016/0306-4522(96)00212-6. [DOI] [PubMed] [Google Scholar]
- 6.Stoll G, Jander S. The role of microglia and macrophages in the pathophysiology of the CNS. Prog Neurobiol. 1999;58:233–247. doi: 10.1016/S0301-0082(98)00083-5. [DOI] [PubMed] [Google Scholar]
- 7.Bauer J, Huitinga I, Zhao W, Lassmann H, Hickey WF, Dijkstra CD. The role of macrophages, perivascular cells, and microglial cells in the pathogenesis of experimental autoimmune encephalomyelitis. Glia. 1995;15:437–446. doi: 10.1002/glia.440150407. [DOI] [PubMed] [Google Scholar]
- 8.Prineas JW, Kwon EE, Cho ES, et al. Immunopathology of secondary-progressive multiple sclerosis. Ann Neurol. 2001;50:646–657. doi: 10.1002/ana.1255. [DOI] [PubMed] [Google Scholar]
- 9.Streit WJ. Microglial response to brain injury: a brief synopsis. Toxicol Pathol. 2000;28:28–30. doi: 10.1177/019262330002800104. [DOI] [PubMed] [Google Scholar]
- 10.Shaw JA, Perry VH, Mellanby J. MHC class II expression by microglia in tetanus toxin-induced experimental epilepsy in the rat. Neuropathol Appl Neurobiol. 1994;20:392–398. doi: 10.1111/j.1365-2990.1994.tb00985.x. [DOI] [PubMed] [Google Scholar]
- 11.Bjartmar C, Kinkel RP, Kidd G, Rudick RA, Trapp BD. Axonal loss in normal-appearing white matter in a patient with acute MS. Neurology. 2001;57:1248–1252. doi: 10.1212/wnl.57.7.1248. [DOI] [PubMed] [Google Scholar]
- 12.Trapp BD, Bo L, Mork S, Chang A. Pathogenesis of tissue injury in MS lesions. J Neuroimmunol. 1999;98:49–56. doi: 10.1016/S0165-5728(99)00081-8. [DOI] [PubMed] [Google Scholar]
- 13.Peterson JW, Bo L, Mork S, Chang A, Trapp BD. Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol. 2001;50:389–400. doi: 10.1002/ana.1123. [DOI] [PubMed] [Google Scholar]
- 14.Banati RB, Newcombe J, Gunn RN, et al. The peripheral benzo-diazepine binding site in the brain in multiple sclerosis: quantitative in vivo imaging of microglia as a measure of disease activity. Brain. 2000;123:2321–2337. doi: 10.1093/brain/123.11.2321. [DOI] [PubMed] [Google Scholar]
- 15.Allen IV, McQuaid S, Mirakhur M, Nevin G. Pathological abnormalities in the normal-appearing white matter in multiple sclerosis. Neurol Sci. 2001;22:141–144. doi: 10.1007/s100720170012. [DOI] [PubMed] [Google Scholar]
- 16.Butovsky O, Landa G, Kunis G, et al. Induction and blockage of oligodendrogenesis by differently activated microglia in an animal model of multiple sclerosis. J Clin Invest. 2006;116:905–915. doi: 10.1172/JCI26836. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Cardona AE, Pioro EP, Sasse ME, et al. Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci. 2006;9:917–924. doi: 10.1038/nn1715. [DOI] [PubMed] [Google Scholar]
- 18.Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science. 2005;308:1314–1318. doi: 10.1126/science.1110647. [DOI] [PubMed] [Google Scholar]
- 19.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 U S A. 1998;95:5779–5784. doi: 10.1073/pnas.95.10.5779. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Mott RT, Ait-Ghezala G, Town T, et al. Neuronal expression of CD22: Novel mechanism for inhibiting microglial proinflammatory cytokine production. Glia. 2004;46:369–379. doi: 10.1002/glia.20009. [DOI] [PubMed] [Google Scholar]
- 21.Hoek RM, Ruuls SR, Murphy CA, et al. Down-regulation of the macrophage lineage through interaction with OX2 (CD200) Science. 2000;290:1768–1771. doi: 10.1126/science.290.5497.1768. [DOI] [PubMed] [Google Scholar]
- 22.Neumann H. Control of glial immune function by neurons. Glia. 2001;36:191–199. doi: 10.1002/glia.1108. [DOI] [PubMed] [Google Scholar]
- 23.Raivich G. Like cops on the beat: the active role of resting microglia. Trends Neurosci. 2005;28:571–573. doi: 10.1016/j.tins.2005.09.001. [DOI] [PubMed] [Google Scholar]
- 24.Davalos D, Grutzendler J, Yang G, et al. ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci. 2005;8:752–758. doi: 10.1038/nn1472. [DOI] [PubMed] [Google Scholar]
- 25.Melchior B, Puntambekar SS, Carson MJ. Microglia and the control of autoreactive T cell responses. Neurochem Int. 2006;49:145–153. doi: 10.1016/j.neuint.2006.04.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Shepard JL, Zon LI. Developmental derivation of embryonic and adult macrophages. Curr Opin Hematol. 2000;7:3–8. doi: 10.1097/00062752-200001000-00002. [DOI] [PubMed] [Google Scholar]
- 27.Levison SW, Druckman SK, Young GM, Basu A. Neural stem cells in the subventricular zone are a source of astrocytes and oligodendrocytes, but not microglia. Dev Neurosci. 2003;25:184–196. doi: 10.1159/000072267. [DOI] [PubMed] [Google Scholar]
- 28.Vallières L, Sawchenko PE. Bone marrow-derived cells that populate the adult mouse brain preserve their hematopoietic identity. J Neurosci. 2003;23:5197–5207. doi: 10.1523/JNEUROSCI.23-12-05197.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Hirasawa T, Ohsawa K, Imai Y, et al. Visualization of microglia in living tissues using Iba1-EGFP transgenic mice. J Neurosci Res. 2005;81:357–362. doi: 10.1002/jnr.20480. [DOI] [PubMed] [Google Scholar]
- 30.Kaur C, Hao AJ, Wu CH, Ling EA. Origin of microglia. Microsc Res Tech. 2001;54:2–9. doi: 10.1002/jemt.1114. [DOI] [PubMed] [Google Scholar]
- 31.Tsuchiya T, Park KC, Toyonaga S, et al. Characterization of microglia induced from mouse embryonic stem cells and their migration into the brain parenchyma. J Neuroimmunol. 2005;160:210–218. doi: 10.1016/j.jneuroim.2004.10.025. [DOI] [PubMed] [Google Scholar]
- 32.Kennedy DW, Abkowitz JL. Kinetics of central nervous system microglial and macrophage engraftment: analysis using a transgenic bone marrow transplantation model. Blood. 1997;90:986–993. [PubMed] [Google Scholar]
- 33.Lassmann H, Schmied M, Vass K, Hickey WF. Bone marrow derived elements and resident microglia in brain inflammation. Glia. 1993;7:19–24. doi: 10.1002/glia.440070106. [DOI] [PubMed] [Google Scholar]
- 34.Matsumoto Y, Fujiwara M. Absence of donor-type major histocompatibility complex class I antigen-bearing microglia in the rat central nervous system of radiation bone marrow chimeras. J Neuroimmunol. 1987;17:71–82. doi: 10.1016/0165-5728(87)90032-4. [DOI] [PubMed] [Google Scholar]
- 35.Becher B, Durell BG, Noelle RJ. IL-23 produced by CNS-resident cells controls T cell encephalitogenicity during the effector phase of experimental autoimmune encephalomyelitis. J Clin Invest. 2003;112:1186–1191. doi: 10.1172/JCI19079. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Hickey WF, Kimura H. Perivascular microglial cells of the CNS are bone marrow-derived and present antigen in vivo. Science. 1988;239:290–292. doi: 10.1126/science.3276004. [DOI] [PubMed] [Google Scholar]
- 37.Wehner T, Bontert M, Eyupoglu I, et al. Bone marrow-derived cells expressing green fluorescent protein under the control of the glial fibrillary acidic protein promoter do not differentiate into astrocytes in vitro and in vivo. J Neurosci. 2003;23:5004–5011. doi: 10.1523/JNEUROSCI.23-12-05004.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Bechmann I, Kwidzinski E, Kovac AD, et al. Turnover of rat brain perivascular cells. Exp Neurol. 2001;168:242–249. doi: 10.1006/exnr.2000.7618. [DOI] [PubMed] [Google Scholar]
- 39.Stalder AK, Ermini F, Bondolfi L, et al. Invasion of hematopoietic cells into the brain of amyloid precursor protein transgenic mice. J Neurosci. 2005;25:11125–11132. doi: 10.1523/JNEUROSCI.2545-05.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Simard AR, Soulet D, Gowing G, Julien JP, Rivest S. Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer’s disease. Neuron. 2006;49:489–502. doi: 10.1016/j.neuron.2006.01.022. [DOI] [PubMed] [Google Scholar]
- 41.Serpe CJ, Kohm AP, Huppenbauer CB, Sanders VM, Jones KJ. Exacerbation of facial motoneuron loss after facial nerve transection in severe combined immunodeficient (scid) mice. J Neurosci. 1999;19:RC7–RC7. doi: 10.1523/JNEUROSCI.19-11-j0004.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Byram SC, Carson MJ, Deboy CA, Serpe CJ, Sanders VM, Jones KJ. CD4+ T cell-mediated neuroprotection requires dual compartment antigen presentation. J Neurosci. 2004;24:4333–4339. doi: 10.1523/JNEUROSCI.5276-03.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Sedgwick JD, Schwender S, Imrich H, Domes R, Butcher GW, ter Meulen V. Isolation and direct characterization of resident microglial cells from the normal and inflamed central nervous system. Proc Natl Acad Sci U S A. 1991;88:7438–7442. doi: 10.1073/pnas.88.16.7438. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Carson MJ, Reilly CR, Sutcliffe JG, Lo D. Mature microglia resemble immature antigen-presenting cells. Glia. 1998;22:72–85. doi: 10.1002/(SICI)1098-1136(199801)22:1<72::AID-GLIA7>3.0.CO;2-A. [DOI] [PubMed] [Google Scholar]
- 45.Priller J, Flugel A, Wehner T, et al. Targeting gene-modified hematopoietic cells to the central nervous system: use of green fluorescent protein uncovers microglial engraftment. Nat Med. 2001;7:1356–1361. doi: 10.1038/nm1201-1356. [DOI] [PubMed] [Google Scholar]
- 46.Schmid CD, Sautkulis LN, Danielson PE, et al. Heterogeneous expression of the triggering receptor expressed on myeloid cells-2 on adult murine microglia. J Neurochem. 2002;83:1309–1320. doi: 10.1046/j.1471-4159.2002.01243.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47.Bédard A, Tremblay P, Chernomoretz A, Vallières L. Identification of genes preferentially expressed by microglia and upregulated during cuprizone-induced inflammation. Glia. 2007;55:777–789. doi: 10.1002/glia.20477. [DOI] [PubMed] [Google Scholar]
- 48.Haynes SE, Hollopeter G, Yang G, et al. The P2Y12 receptor regulates microglial activation by extracellular nucleotides. Nat Neurosci. 2006;9:1512–1519. doi: 10.1038/nn1805. [DOI] [PubMed] [Google Scholar]
- 49.Lawson LJ, Perry VH, Dri P, Gordon S. Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience. 1990;39:151–170. doi: 10.1016/0306-4522(90)90229-W. [DOI] [PubMed] [Google Scholar]
- 50.Lawson LJ, Matyszak MK, Perry VH. Lessons from microglia in special sites. Clin Neuropathol. 1993;12:310–313. [PubMed] [Google Scholar]
- 51.Carson MJ. Microglia as liaisons between the immune and central nervous systems: functional implications for multiple sclerosis. Glia. 2002;40:218–231. doi: 10.1002/glia.10145. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 52.Moran LB, Duke DC, Graeber MB. The microglial gene regulatory network activated by interferon-gamma. J Neuroimmunol. 2007;183:1–6. doi: 10.1016/j.jneuroim.2006.10.023. [DOI] [PubMed] [Google Scholar]
- 53.Lund S, Christensen KV, Hedtjäm M, et al. The dynamics of the LPS triggered inflammatory response of murine microglia under different culture and in vivo conditions. J Neuroimmunol. 2006;180:71–87. doi: 10.1016/j.jneuroim.2006.07.007. [DOI] [PubMed] [Google Scholar]
- 54.Reed MJ, Puolakkainen P, Lane TF, Dickerson D, Bomstein P, Sage EH. Differential expression of SPARC and thrombospondin 1 in wound repair: immunolocalization and in situ hybridization. J Histochem Cytochem. 1993;41:1467–1477. doi: 10.1177/41.10.8245406. [DOI] [PubMed] [Google Scholar]
- 55.Carson MJ, Doose JM, Melchior B, Schmid CD, Ploix CC. CNS immune privilege: hiding in plain sight. Immunol Rev. 2006;213:48–65. doi: 10.1111/j.1600-065X.2006.00441.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 56.Paloneva J, Autti T, Raininko R, et al. CNS manifestations of Nasu-Hakola disease: a frontal dementia with bone cysts. Neurology. 2001;56:1552–1558. doi: 10.1212/wnl.56.11.1552. [DOI] [PubMed] [Google Scholar]
- 57.Daws MR, Sullam PM, Niemi EC, Chen TT, Tchao NK, Seaman WE. Pattern recognition by TREM-2: binding of anionic ligands. J Immunol. 2003;171:594–599. doi: 10.4049/jimmunol.171.2.594. [DOI] [PubMed] [Google Scholar]
- 58.Kiialainen A, Hovanes K, Paloneva J, Kopra O, Peltonen L. Dap12 and Trem2, molecules involved in innate immunity and neurodegeneration, are co-expressed in the CNS. Neurobiol Dis. 2005;18:314–322. doi: 10.1016/j.nbd.2004.09.007. [DOI] [PubMed] [Google Scholar]
- 59.Bouchon A, Hemández-Munain C, Cella M, Colonna M. A DAP12-mediated pathway regulates expression of CC chemokine receptor 7 and maturation of human dendritic cells. J Exp Med. 2001;194:1111–1122. doi: 10.1084/jem.194.8.1111. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 60.Cella M, Buonsanti C, Strader C, Kondo T, Salmaggi A, Colonna M. Impaired differentiation of osteoclasts in TREM-2-deficient individuals. J Exp Med. 2003;198:645–651. doi: 10.1084/jem.20022220. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 61.Takahashi K, Prinz M, Stagi M, Chechneva O, Neumann H. TREM2-transduced myeloid precursors mediate nervous tissue debris clearance and facilitate recovery in an animal model of multiple sclerosis. PLoS Med. 2007;4:el24–el24. doi: 10.1371/journal.pmed.0040124. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 62.Piccio L, Buonsanti C, Mariani M, et al. Blockade of TREM-2 exacerbates experimental autoimmune encephalomyelitis. Eur J Immunol. 2007;37:1290–1301. doi: 10.1002/eji.200636837. [DOI] [PubMed] [Google Scholar]
- 63.Streit WJ. Microglia and neuroprotection: implications for Alzheimer’s disease. Brain Res Brain Res Rev. 2005;48:234–239. doi: 10.1016/j.brainresrev.2004.12.013. [DOI] [PubMed] [Google Scholar]
- 64.Bilousova TV, Rusakov DA, Ethell DW, Ethell IM. Matrix metalloproteinase-7 disrupts dendritic spines in hippocampal neurons through NMDA receptor activation. J Neurochem. 2006;97:44–56. doi: 10.1111/j.1471-4159.2006.03701.x. [DOI] [PMC free article] [PubMed] [Google Scholar]