1932

Abstract

Microglia, the resident immune cells of the central nervous system (CNS), are primarily derived from the embryonic yolk sac and make their way to the CNS during early development. They play key physiological and immunological roles across the life span, throughout health, injury, and disease. Recent transcriptomic studies have identified gene transcript signatures expressed by microglia that may provide the foundation for unprecedented insights into their functions. Microglial gene expression signatures can help distinguish them from macrophage cell types to a reasonable degree of certainty, depending on the context. Microglial expression patterns further suggest a heterogeneous population comprised of many states that vary according to the spatiotemporal context. Microglial diversity is most pronounced during development, when extensive CNS remodeling takes place, and following disease or injury. A next step of importance for the field will be to identify the functional roles performed by these various microglial states, with the perspective of targeting them therapeutically.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-genet-022223-093643
2023-11-27
2024-05-04
Loading full text...

Full text loading...

/deliver/fulltext/genet/57/1/annurev-genet-022223-093643.html?itemId=/content/journals/10.1146/annurev-genet-022223-093643&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Absinta M, Maric D, Gharagozloo M, Garton T, Smith MD et al. 2021. A lymphocyte-microglia-astrocyte axis in chronic active multiple sclerosis. Nature 597:7878709–14
    [Google Scholar]
  2. 2.
    Anderson SR, Roberts JM, Ghena N, Irvin EA, Schwakopf J et al. 2022. Neuronal apoptosis drives remodeling states of microglia and shifts in survival pathway dependence. eLife 11:e76564
    [Google Scholar]
  3. 3.
    Anderson SR, Roberts JM, Zhang J, Steele MR, Romero CO et al. 2019. Developmental apoptosis promotes a disease-related gene signature and independence from CSF1R signaling in retinal microglia. Cell Rep. 27:72002–13.e5
    [Google Scholar]
  4. 4.
    Augusto-Oliveira M, Arrifano GP, Delage CI, Tremblay M-È, Crespo-Lopez ME, Verkhratsky A. 2022. Plasticity of microglia. Biol. Rev. Camb. Philos. Soc. 97:1217–50
    [Google Scholar]
  5. 5.
    Barko K, Shelton M, Xue X, Afriyie-Agyemang Y, Puig S et al. 2022. Brain region- and sex-specific transcriptional profiles of microglia. Front. Psychiatry 13:945548
    [Google Scholar]
  6. 6.
    Bartolo ND, Mortimer N, Manter MA, Sanchez N, Riley M et al. 2022. Identification and prioritization of PET neuroimaging targets for microglial phenotypes associated with microglial activity in Alzheimer's disease. ACS Chem. Neurosci. 13:243641–60
    [Google Scholar]
  7. 7.
    Benmamar-Badel A, Owens T, Wlodarczyk A. 2020. Protective microglial subset in development, aging, and disease: lessons from transcriptomic studies. Front. Immunol. 11:430
    [Google Scholar]
  8. 8.
    Bennett ML, Bennett FC, Liddelow SA, Ajami B, Zamanian JL et al. 2016. New tools for studying microglia in the mouse and human CNS. PNAS 113:12E1738–46
    [Google Scholar]
  9. 9.
    Bisht K, Sharma KP, Lecours C, Sánchez MG, El Hajj H et al. 2016. Dark microglia: a new phenotype predominantly associated with pathological states. Glia 64:5826–39
    [Google Scholar]
  10. 10.
    Bordeleau M, Carrier M, Luheshi GN, Tremblay M-È. 2019. Microglia along sex lines: from brain colonization, maturation and function, to implication in neurodevelopmental disorders. Semin. Cell Dev. Biol. 94:152–63
    [Google Scholar]
  11. 11.
    Butovsky O, Jedrychowski MP, Moore CS, Cialic R, Lanser AJ et al. 2014. Identification of a unique TGF-β-dependent molecular and functional signature in microglia. Nat. Neurosci. 17:1131–43
    [Google Scholar]
  12. 12.
    Chappell-Maor L, Kolesnikov M, Kim J-S, Shemer A, Haimon Z et al. 2020. Comparative analysis of CreER transgenic mice for the study of brain macrophages: a case study. Eur. J. Immunol. 50:3353–62
    [Google Scholar]
  13. 13.
    De Andrade Costa A, Chatterjee J, Cobb O, Sanapala S, Scheaffer S et al. 2022. RNA sequence analysis reveals ITGAL/CD11A as a stromal regulator of murine low-grade glioma growth. Neuro-Oncology 24:114–26
    [Google Scholar]
  14. 14.
    De Felice E, Gonçalves de Andrade E, Golia MT, González Ibáñez F, Khakpour M et al. 2022. Microglial diversity along the hippocampal longitudinal axis impacts synaptic plasticity in adult male mice under homeostatic conditions. J. Neuroinflamm. 19:1292
    [Google Scholar]
  15. 15.
    Delage CI, Šimončičová E, Tremblay M-È. 2021. Microglial heterogeneity in aging and Alzheimer's disease: Is sex relevant?. J. Pharmacol. Sci. 146:3169–81
    [Google Scholar]
  16. 16.
    Dong Y, Jain RW, Lozinski BM, D'Mello C, Visser F et al. 2022. Single-cell and spatial RNA sequencing identify perturbators of microglial functions with aging. Nat. Aging 2:6508–25
    [Google Scholar]
  17. 17.
    El Hajj H, Savage JC, Bisht K, Parent M, Vallières L et al. 2019. Ultrastructural evidence of microglial heterogeneity in Alzheimer's disease amyloid pathology. J. Neuroinflamm. 16:187
    [Google Scholar]
  18. 18.
    Faust TE, Feinberg PA, O'Connor C, Kawaguchi R, Chan A et al. 2023. A comparative analysis of microglial inducible Cre lines. bioRxiv 2023.01.09.523268. https://doi.org/10.1101/2023.01.09.523268
  19. 19.
    Ginhoux F, Greter M, Leboeuf M, Nandi S, See P et al. 2010. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330:6005841–45
    [Google Scholar]
  20. 20.
    Gosselin D, Skola D, Coufal NG, Holtman IR, Schlachetzki JCM et al. 2017. An environment-dependent transcriptional network specifies human microglia identity. Science 356:6344eaal3222
    [Google Scholar]
  21. 21.
    Grabert K, Michoel T, Karavolos MH, Clohisey S, Baillie JK et al. 2016. Microglial brain region-dependent diversity and selective regional sensitivities to aging. Nat. Neurosci. 19:3504–16
    [Google Scholar]
  22. 22.
    Grajchen E, Hendriks JJA, Bogie JFJ. 2018. The physiology of foamy phagocytes in multiple sclerosis. Acta Neuropathol. Commun. 6:1124
    [Google Scholar]
  23. 23.
    Guma E, Bordeleau M, González Ibáñez F, Picard K, Snook E et al. 2022. Differential effects of early or late exposure to prenatal maternal immune activation on mouse embryonic neurodevelopment. PNAS 119:12e2114545119
    [Google Scholar]
  24. 24.
    Guneykaya D, Ivanov A, Hernandez DP, Haage V, Wojtas B et al. 2018. Transcriptional and translational differences of microglia from male and female brains. Cell Rep. 24:102773–83.e6
    [Google Scholar]
  25. 25.
    Hagemeyer N, Hanft K-M, Akriditou M-A, Unger N, Park ES et al. 2017. Microglia contribute to normal myelinogenesis and to oligodendrocyte progenitor maintenance during adulthood. Acta Neuropathol. 134:3441–58
    [Google Scholar]
  26. 26.
    Hammond TR, Dufort C, Dissing-Olesen L, Giera S, Young A et al. 2019. Single-cell RNA sequencing of microglia throughout the mouse lifespan and in the injured brain reveals complex cell-state changes. Immunity 50:1253–71.e6
    [Google Scholar]
  27. 27.
    Han CZ, Li RZ, Hansen E, Bennett HR, Poirion O et al. 2021. Gene regulatory networks underlying human microglia maturation. bioRxiv 2021.06.02.446636. https://doi.org/10.1101/2021.06.02.446636
  28. 28.
    Harry GJ, Pont-Lezica L 2014. Developmental vascularization, neurogenesis, myelination, and astrogliogenesis. Microglia in Health and Disease M-È Tremblay, A Sierra 193–221. New York: Springer
    [Google Scholar]
  29. 29.
    Hickman SE, Kingery ND, Ohsumi T, Borowsky M, Wang L et al. 2013. The microglial sensome revealed by direct RNA sequencing. Nat. Neurosci. 16:121896–905
    [Google Scholar]
  30. 30.
    Hoeffel G, Ginhoux F. 2018. Fetal monocytes and the origins of tissue-resident macrophages. Cell Immunol. 330:5–15
    [Google Scholar]
  31. 31.
    Hoghooghi V, Palmer AL, Frederick A, Jiang Y, Merkens JE et al. 2020. Cystatin C plays a sex-dependent detrimental role in experimental autoimmune encephalomyelitis. Cell Rep. 33:1108236
    [Google Scholar]
  32. 32.
    Houser MC, Uriarte Huarte O, Wallings RL, Keating CE, MacPherson KP et al. 2022. Progranulin loss results in sex-dependent dysregulation of the peripheral and central immune system. Front. Immunol. 13:1056417
    [Google Scholar]
  33. 33.
    Jones EV, Bernardinelli Y, Zarruk JG, Chierzi S, Murai KK. 2018. SPARC and GluA1-containing AMPA receptors promote neuronal health following CNS injury. Front. Cell Neurosci. 12:22
    [Google Scholar]
  34. 34.
    Kamphuis W, Kooijman L, Schetters S, Orre M, Hol EM. 2016. Transcriptional profiling of CD11c-positive microglia accumulating around amyloid plaques in a mouse model for Alzheimer's disease. Biochim. Biophys. Acta Mol. Basis Dis. 1862:101847–60
    [Google Scholar]
  35. 35.
    Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R et al. 2017. A unique microglia type associated with restricting development of Alzheimer's disease. Cell 169:71276–90.e17
    [Google Scholar]
  36. 36.
    Kierdorf K, Erny D, Goldmann T, Sander V, Schulz C et al. 2013. Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nat. Neurosci. 16:3273–80
    [Google Scholar]
  37. 37.
    Krasemann S, Madore C, Cialic R, Baufeld C, Calcagno N et al. 2017. The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47:3566–81.e9
    [Google Scholar]
  38. 38.
    Li Q, Cheng Z, Zhou L, Darmanis S, Neff NF et al. 2019. Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing. Neuron 101:2207–23.e10
    [Google Scholar]
  39. 39.
    Limone F, Mordes DA, Couto A, Joseph BJ, Mitchell J et al. 2023. Single-nucleus sequencing reveals enriched expression of genetic risk factors in extratelencephalic neurons sensitive to degeneration in ALS. bioRxiv 2021.07.12.452054. https://www.biorxiv.org/content/10.1101/2021.07.12.452054v2
  40. 40.
    Lin G, Chai J, Yuan S, Mai C, Cai L et al. 2016. VennPainter: a tool for the comparison and identification of candidate genes based on Venn diagrams. PLOS ONE 11:4e0154315
    [Google Scholar]
  41. 41.
    Lynch MA. 2022. Exploring sex-related differences in microglia may be a game-changer in precision medicine. Front. Aging Neurosci. 14:868448
    [Google Scholar]
  42. 42.
    Manjally AV, Tay TL. 2022. Attack of the clones: microglia in health and disease. Front. Cell Neurosci. 16:831747
    [Google Scholar]
  43. 43.
    Marschallinger J, Iram T, Zardeneta M, Lee SE, Lehallier B et al. 2020. Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain. Nat. Neurosci. 23:2194–208
    [Google Scholar]
  44. 44.
    Marsh SE, Walker AJ, Kamath T, Dissing-Olesen L, Hammond TR et al. 2022. Dissection of artifactual and confounding glial signatures by single-cell sequencing of mouse and human brain. Nat. Neurosci. 25:3306–16
    [Google Scholar]
  45. 45.
    Mass E, Nimmerjahn F, Kierdorf K, Schlitzer A. 2023. Tissue-specific macrophages: how they develop and choreograph tissue biology. Nat. Rev. Immunol. https://doi.org/10.1038/s41577-023-00848-y
    [Google Scholar]
  46. 46.
    Masuda T, Sankowski R, Staszewski O, Böttcher C, Amann L et al. 2019. Spatial and temporal heterogeneity of mouse and human microglia at single-cell resolution. Nature 566:7744388–92
    [Google Scholar]
  47. 47.
    Matcovitch-Natan O, Winter DR, Giladi A, Vargas Aguilar S, Spinrad A et al. 2016. Microglia development follows a stepwise program to regulate brain homeostasis. Science 353:6301aad8670
    [Google Scholar]
  48. 48.
    Murray CJ, Vecchiarelli HA, Tremblay M-È et al. 2023. Enhancing axonal myelination in seniors: a review exploring the potential impact cannabis has on myelination in the aged brain. Front. Aging Neurosci. 15:1119552
    [Google Scholar]
  49. 49.
    Paolicelli RC, Sierra A, Stevens B, Tremblay M-È, Aguzzi A et al. 2022. Microglia states and nomenclature: a field at its crossroads. Neuron 110:213458–83
    [Google Scholar]
  50. 50.
    Qie J, Liu Y, Wang Y, Zhang F, Qin Z et al. 2022. Integrated proteomic and transcriptomic landscape of macrophages in mouse tissues. Nat. Commun. 13:7389
    [Google Scholar]
  51. 51.
    Saade M, Araujo de Souza G, Scavone C, Kinoshita PF. 2021. The role of GPNMB in inflammation. Front. Immunol. 12:674739
    [Google Scholar]
  52. 52.
    Safaiyan S, Besson-Girard S, Kaya T, Cantuti-Castelvetri L, Liu L et al. 2021. White matter aging drives microglial diversity. Neuron 109:71100–17.e10
    [Google Scholar]
  53. 53.
    Sala Frigerio C, Wolfs L, Fattorelli N, Thrupp N, Voytyuk I et al. 2019. The major risk factors for Alzheimer's disease: Age, sex, and genes modulate the microglia response to Aβ plaques. Cell Rep. 27:41293–306.e6
    [Google Scholar]
  54. 54.
    Sankowski R, Böttcher C, Masuda T, Geirsdottir L, Sagar et al. 2019. Mapping microglia states in the human brain through the integration of high-dimensional techniques. Nat. Neurosci. 22:122098–110
    [Google Scholar]
  55. 55.
    Satoh J, Kino Y, Asahina N, Takitani M, Miyoshi J et al. 2016. TMEM119 marks a subset of microglia in the human brain. Neuropathology 36:139–49
    [Google Scholar]
  56. 56.
    Savage JC, Picard K, González-Ibáñez F, Tremblay M-È. 2018. A brief history of microglial ultrastructure: distinctive features, phenotypes, and functions discovered over the past 60years by electron microscopy. Front. Immunol. 9:803
    [Google Scholar]
  57. 57.
    Schulz C, Perdiguero EG, Chorro L, Szabo-Rogers H, Cagnard N et al. 2012. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336:607786–90
    [Google Scholar]
  58. 58.
    Sierra A, Paolicelli RC, Kettenmann H. 2019. Cien años de microglía: milestones in a century of microglial research. Trends Neurosci. 42:11778–92
    [Google Scholar]
  59. 59.
    Sierra A, Tremblay M-È. 2014. Adult neurogenesis, learning and memory. Microglia in Health and Disease M-È Tremblay, A Sierra 249–71. New York: Springer
    [Google Scholar]
  60. 60.
    Šimončičová E, Gonçalves de Andrade E, Vecchiarelli HA, Awogbindin IO, Delage CI, Tremblay M-È. 2022. Present and future of microglial pharmacology. Trends Pharmacol. Sci. 43:8669–85
    [Google Scholar]
  61. 61.
    Srinivasan K, Friedman BA, Etxeberria A, Huntley MA, van der Brug MP et al. 2020. Alzheimer's patient microglia exhibit enhanced aging and unique transcriptional activation. Cell Rep. 31:13107843
    [Google Scholar]
  62. 62.
    St-Pierre M-K, Carrier M, González Ibáñez F, Šimončičová E, Wallman M-J et al. 2022. Ultrastructural characterization of dark microglia during aging in a mouse model of Alzheimer's disease pathology and in human post-mortem brain samples. J. Neuroinflamm. 19:1235
    [Google Scholar]
  63. 63.
    Stratoulias V, Venero JL, Tremblay M-È, Joseph B. 2019. Microglial subtypes: diversity within the microglial community. EMBO J. 38:17e101997
    [Google Scholar]
  64. 64.
    Stremmel C, Schuchert R, Wagner F, Thaler R, Weinberger T et al. 2018. Yolk sac macrophage progenitors traffic to the embryo during defined stages of development. Nat. Commun. 9:175
    [Google Scholar]
  65. 65.
    Strunz M, Jarrell JT, Cohen DS, Rosin ER, Vanderburg CR, Huang X. 2019. Modulation of SPARC/Hevin proteins in Alzheimer's disease brain injury. J. Alzheimers Dis. 68:2695–710
    [Google Scholar]
  66. 66.
    Tay TL, Carrier M, Tremblay M-È. 2019. Physiology of microglia. Adv. Exp. Med. Biol. 1175:129–48
    [Google Scholar]
  67. 67.
    Tay TL, Mai D, Dautzenberg J, Fernández-Klett F, Lin G et al. 2017. A new fate mapping system reveals context-dependent random or clonal expansion of microglia. Nat. Neurosci. 20:6793–803
    [Google Scholar]
  68. 68.
    Thrupp N, Sala Frigerio C, Wolfs L, Skene NG, Fattorelli N et al. 2020. Single-nucleus RNA-seq is not suitable for detection of microglial activation genes in humans. Cell Rep. 32:13108189
    [Google Scholar]
  69. 69.
    Tremblay M-È, Marker DF, Puccini JM, Muly EC, Lu S-M, Gelbard HA. 2013. Ultrastructure of microglia-synapse interactions in the HIV-1 Tat-injected murine central nervous system. Commun. Integr. Biol. 6:6e27670
    [Google Scholar]
  70. 70.
    Tremblay M-È, Paolicelli RC, Stevens B, Wake H, Bessis A 2014. Developing and mature synapses. Microglia in Health and Disease M-È Tremblay, A Sierra 223–48. New York: Springer
    [Google Scholar]
  71. 71.
    Tremblay M-È, Zettel ML, Ison JR, Allen PD, Majewska AK. 2012. Effects of aging and sensory loss on glial cells in mouse visual and auditory cortices. Glia 60:4541–58
    [Google Scholar]
  72. 72.
    VanRyzin JW, Arambula SE, Ashton SE, Blanchard AC, Burzinski MD et al. 2021. Generation of an Iba1-EGFP transgenic rat for the study of microglia in an outbred rodent strain. eNeuro 8:5ENEURO.0026-21.2021
    [Google Scholar]
  73. 73.
    Vasek MJ, Mueller S, Fass SB, Deajon-Jackson JD, Liu Y et al. 2023. Local translation in microglial processes is required for efficient phagocytosis. Nat. Neurosci. https://doi.org/10.1038/s41593-023-01353-0
    [Google Scholar]
  74. 74.
    Vecchiarelli HA, Šimončičová E, Tremblay M-È. 2021. Microglial involvement with psychiatric diseases. Psychiatr. Times 38:132–36
    [Google Scholar]
  75. 75.
    Vecchiarelli HA, Tremblay M-È. 2023. Local translation in microglial processes. Nat. Neurosci. 26:1140–42
    [Google Scholar]
  76. 76.
    Watanabe S, Alexander M, Misharin AV, Budinger GRS. 2019. The role of macrophages in the resolution of inflammation. J. Clin. Invest. 129:72619–28
    [Google Scholar]
  77. 77.
    Wishart CL, Spiteri AG, Locatelli G, King NJC. 2022. Integrating transcriptomic datasets across neurological disease identifies unique myeloid subpopulations driving disease-specific signatures. Glia 71:4904–25
    [Google Scholar]
  78. 78.
    Wlodarczyk A, Holtman IR, Krueger M, Yogev N, Bruttger J et al. 2017. A novel microglial subset plays a key role in myelinogenesis in developing brain. EMBO J. 36:223292–308
    [Google Scholar]
  79. 79.
    Yong VW. 2022. Microglia in multiple sclerosis: Protectors turn destroyers. Neuron 110:213534–48
    [Google Scholar]
  80. 80.
    Young AMH, Kumasaka N, Calvert F, Hammond TR, Knights A et al. 2021. A map of transcriptional heterogeneity and regulatory variation in human microglia. Nat. Genet. 53:6861–68
    [Google Scholar]
  81. 81.
    Zheng J, Ru W, Adolacion JR, Spurgat MS, Liu X et al. 2021. Single-cell RNA-seq analysis reveals compartment-specific heterogeneity and plasticity of microglia. iScience 24:3102186
    [Google Scholar]
/content/journals/10.1146/annurev-genet-022223-093643
Loading
/content/journals/10.1146/annurev-genet-022223-093643
Loading

Data & Media loading...

Supplemental Material

Supplementary Data

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error