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Mechanisms of myeloid cell entry to the healthy and diseased central nervous system

Nature Immunology volume 24, pages 393–407 (2023)Cite this article

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Abstract

Myeloid cells in the central nervous system (CNS), such as microglia, CNS-associated macrophages (CAMs), dendritic cells and monocytes, are vital for steady-state immune homeostasis as well as the resolution of tissue damage during brain development or disease-related pathology. The complementary usage of multimodal high-throughput and high-dimensional single-cell technologies along with recent advances in cell-fate mapping has revealed remarkable myeloid cell heterogeneity in the CNS. Despite the establishment of extensive expression profiles revealing myeloid cell multiplicity, the local anatomical conditions for the temporal- and spatial-dependent cellular engraftment are poorly understood. Here we highlight recent discoveries of the context-dependent mechanisms of myeloid cell migration and settlement into distinct subtissular structures in the CNS. These insights offer better understanding of the factors needed for compartment-specific myeloid cell recruitment, integration and residence during development and perturbation, which may lead to better treatment of CNS diseases.

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Fig. 1: Cellular composition of CNS macrophage niches.
Fig. 2: Timeline of CNS interface development in mice.
Fig. 3: Settlement of CNS myeloid cells into the developing CNS.
Fig. 4: Recruitment of myeloid cells following depletion and during CNS inflammation.

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References

  1. Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010). In this seminal work, the YS origin of microglia was established using fate-mapping mouse models. This marked the beginning of the discovery of the embryonic origin of many tissue-resident macrophages.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Goldmann, T. et al. Origin, fate and dynamics of macrophages at central nervous system interfaces. Nat. Immunol. 17, 797–805 (2016). This paper demonstrated that leptomeningeal and perivascular macrophages are YS derived and are not replaced by HSC-derived cells in mice.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Stremmel, C. et al. Yolk sac macrophage progenitors traffic to the embryo during defined stages of development. Nat. Commun. 9, 75 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Kierdorf, K. et al. Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nat. Neurosci. 16, 273–280 (2013).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  7. 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). This study is an important resource in the field as it provides a very detailed and thorough analysis of the transcription profiles of various CNS macrophage subsets. It also describes how Kolmer’s epiplexus cells share many features of microglia.

    Article  PubMed  Google Scholar 

  8. Prinz, M., Masuda, T., Wheeler, M. A. & Quintana, F. J. Microglia and central nervous system-associated macrophages—from origin to disease modulation. Annu. Rev. Immunol. 39, 251–277 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Morrison, S. J. & Scadden, D. T. The bone marrow niche for haematopoietic stem cells. Nature 505, 327–334 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Guilliams, M. & Scott, C. L. Does niche competition determine the origin of tissue-resident macrophages? Nat. Rev. Immunol. 17, 451–460 (2017).

    Article  CAS  PubMed  Google Scholar 

  11. Bouchaud, C. & Bosler, O. The circumventricular organs of the mammalian brain with special reference to monoaminergic innervation. In International Review of Cytology Vol. 105, 283–327 (Elsevier, 1986).

  12. Daneman, R. & Prat, A. The blood–brain barrier. Cold Spring Harb. Perspect. Biol. 7, a020412 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Weller, R. O., Sharp, M. M., Christodoulides, M., Carare, R. O. & Møllgård, K. The meninges as barriers and facilitators for the movement of fluid, cells and pathogens related to the rodent and human CNS. Acta Neuropathol. 135, 363–385 (2018).

    Article  CAS  PubMed  Google Scholar 

  14. Engelhardt, B., Vajkoczy, P. & Weller, R. O. The movers and shapers in immune privilege of the CNS. Nat. Immunol. 18, 123–131 (2017).

    Article  CAS  PubMed  Google Scholar 

  15. Owens, T., Bechmann, I. & Engelhardt, B. Perivascular spaces and the two steps to neuroinflammation. J. Neuropathol. Exp. Neurol. 67, 1113–1121 (2008).

    Article  PubMed  Google Scholar 

  16. Munro, D. A. D., Movahedi, K. & Priller, J. Macrophage compartmentalization in the brain and cerebrospinal fluid system. Sci. Immunol. 7, eabk0391 (2022).

    Article  CAS  PubMed  Google Scholar 

  17. Guilliams, M., Thierry, G. R., Bonnardel, J. & Bajenoff, M. Establishment and maintenance of the macrophage niche. Immunity 52, 434–451 (2020). This review article nicely illustrates the concept of the macrophage niche and provides several examples of known niche factors and cellular sources of such factors.

    Article  CAS  PubMed  Google Scholar 

  18. Derk, J., Jones, H. E., Como, C., Pawlikowski, B. & Siegenthaler, J. A. Living on the edge of the CNS: meninges cell diversity in health and disease. Front. Cell. Neurosci. 15, 703944 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Louveau, A. et al. Structural and functional features of central nervous system lymphatic vessels. Nature 523, 337–341 (2015). This paper shows that lymphatic vessels in the dura mater drain CNS-derived antigens into the cervical lymph nodes, provoking a paradigm shift in our understanding of CNS immune reactions and CNS immune privilege.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 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).

    Article  Google Scholar 

  21. Rustenhoven, J. et al. Functional characterization of the dural sinuses as a neuroimmune interface. Cell 184, 1000–1016 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sato, T., Konishi, H., Tamada, H., Nishiwaki, K. & Kiyama, H. Morphology, localization, and postnatal development of dural macrophages. Cell Tissue Res. 384, 49–58 (2021).

    Article  CAS  PubMed  Google Scholar 

  23. Brioschi, S. et al. Heterogeneity of meningeal B cells reveals a lymphopoietic niche at the CNS borders. Science 373, eabf9277 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Merlini, A. et al. Distinct roles of the meningeal layers in CNS autoimmunity. Nat. Neurosci. 25, 887–899 (2022).

    Article  CAS  PubMed  Google Scholar 

  25. Jordão, M. J. C. et al. Single-cell profiling identifies myeloid cell subsets with distinct fates during neuroinflammation. Science 363, eaat7554 (2019).

    Article  PubMed  Google Scholar 

  26. Ransohoff, R. M. & Engelhardt, B. The anatomical and cellular basis of immune surveillance in the central nervous system. Nat. Rev. Immunol. 12, 623–635 (2012).

    Article  CAS  PubMed  Google Scholar 

  27. Zhang, E. T., Inman, C. B. & Weller, R. O. Interrelationships of the pia mater and the perivascular (Virchow–Robin) spaces in the human cerebrum. J. Anat. 170, 111–123 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Masuda, T. et al. Specification of CNS macrophage subsets occurs postnatally in defined niches. Nature 604, 740–748 (2022).

    Article  CAS  PubMed  Google Scholar 

  29. Faraco, G. et al. Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension. J. Clin. Invest. 126, 4674–4689 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Lun, M. P., Monuki, E. S. & Lehtinen, M. K. Development and functions of the choroid plexus–cerebrospinal fluid system. Nat. Rev. Neurosci. 16, 445–457 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Dani, N. et al. A cellular and spatial map of the choroid plexus across brain ventricles and ages. Cell 184, 3056–3074 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Tischfield, M. A. et al. Cerebral vein malformations result from loss of Twist1 expression and BMP signaling from skull progenitor cells and dura. Dev. Cell 42, 445–461 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Dasgupta, K., Chung, J. U., Asam, K. & Jeong, J. Molecular patterning of the embryonic cranial mesenchyme revealed by genome-wide transcriptional profiling. Dev. Biol. 455, 434–448 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. DeSisto, J. et al. Single-cell transcriptomic analyses of the developing meninges reveal meningeal fibroblast diversity and function. Dev. Cell 54, 43–59 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. McLone, D. G. & Bondareff, W. Developmental morphology of the subarachnoid space and contiguous structures in the mouse. Am. J. Anat. 142, 273–293 (1975).

    Article  CAS  PubMed  Google Scholar 

  36. Dasgupta, K. & Jeong, J. Developmental biology of the meninges. Genesis 57, e23288 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Gupta, A., Rarick, K. R. & Ramchandran, R. Established, new and emerging concepts in brain vascular development. Front. Physiol. 12, 636736 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Blanchette, M. & Daneman, R. Formation and maintenance of the BBB. Mech. Dev. 138, 8–16 (2015).

    Article  CAS  PubMed  Google Scholar 

  39. Daneman, R., Zhou, L., Kebede, A. A. & Barres, B. A. Pericytes are required for blood–brain barrier integrity during embryogenesis. Nature 468, 562–566 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Yang, Y., Higashimori, H. & Morel, L. Developmental maturation of astrocytes and pathogenesis of neurodevelopmental disorders. J. Neurodev. Disord. 5, 22 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Hoeffel, G. et al. C-Myb+ erythro-myeloid progenitor-derived fetal monocytes give rise to adult tissue-resident macrophages. Immunity 42, 665–678 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Vanlandewijck, M. et al. A molecular atlas of cell types and zonation in the brain vasculature. Nature 554, 475–480 (2018). An important work that provides a valuable resource of single-cell RNA-sequencing data from diverse CNS cell types. It shows heterogeneity of cell types along the brain vasculature tree (zonation) and describes perivascular fibroblast-like cells.

    Article  CAS  PubMed  Google Scholar 

  43. Saunders, A. et al. Molecular diversity and specializations among the cells of the adult mouse brain. Cell 174, 1015–1030 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Garcia, F. J. et al. Single-cell dissection of the human brain vasculature. Nature 603, 893–899 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Yang, A. C. et al. A human brain vascular atlas reveals diverse mediators of Alzheimer’s risk. Nature 603, 885–892 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Månberg, A. et al. Altered perivascular fibroblast activity precedes ALS disease onset. Nat. Med. 27, 640–646 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Hupe, M. et al. Gene expression profiles of brain endothelial cells during embryonic development at bulk and single-cell levels. Sci. Signal. 10, eaag2476 (2017).

    Article  PubMed  Google Scholar 

  48. Dorrier, C. E., Jones, H. E., Pintarić, L., Siegenthaler, J. A. & Daneman, R. Emerging roles for CNS fibroblasts in health, injury and disease. Nat. Rev. Neurosci. 23, 23–34 (2022).

    Article  CAS  PubMed  Google Scholar 

  49. Krausgruber, T. et al. Structural cells are key regulators of organ-specific immune responses. Nature 583, 296–302 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Mass, E. Delineating the origins, developmental programs and homeostatic functions of tissue-resident macrophages. Int. Immunol. 30, 493–501 (2018).

    Article  CAS  PubMed  Google Scholar 

  51. Yona, S. et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38, 79–91 (2013).

    Article  CAS  PubMed  Google Scholar 

  52. Utz, S. G. et al. Early fate defines microglia and non-parenchymal brain macrophage development. Cell 181, 557–573 (2020).

    Article  CAS  PubMed  Google Scholar 

  53. Mass, E. et al. Specification of tissue-resident macrophages during organogenesis. Science 353, aaf4238 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Schulz, C. et al. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336, 86–90 (2012).

    Article  CAS  PubMed  Google Scholar 

  55. Swinnen, N. et al. Complex invasion pattern of the cerebral cortex by microglial cells during development of the mouse embryo. Glia 61, 150–163 (2013).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  57. Lelli, A. et al. The NADPH oxidase Nox2 regulates VEGFR1/CSF-1R-mediated microglial chemotaxis and promotes early postnatal infiltration of phagocytes in the subventricular zone of the mouse cerebral cortex. Glia 61, 1542–1555 (2013).

    Article  PubMed  Google Scholar 

  58. Arnò, B. et al. Neural progenitor cells orchestrate microglia migration and positioning into the developing cortex. Nat. Commun. 5, 5611 (2014).

    Article  PubMed  Google Scholar 

  59. Thion, M. S. et al. Microbiome influences prenatal and adult microglia in a sex-specific manner. Cell 172, 500–516 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Werner, Y. et al. Cxcr4 distinguishes HSC-derived monocytes from microglia and reveals monocyte immune responses to experimental stroke. Nat. Neurosci. 23, 351–362 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Calderwood, D. A., Campbell, I. D. & Critchley, D. R. Talins and kindlins: partners in integrin-mediated adhesion. Nat. Rev. Mol. Cell Biol. 14, 503–517 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Domenga, V. et al. Notch3 is required for arterial identity and maturation of vascular smooth muscle cells. Genes Dev. 18, 2730–2735 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Munro, D. A. D. et al. CNS macrophages differentially rely on an intronic Csf1r enhancer for their development. Development 147, dev194449 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Cugurra, A. et al. Skull and vertebral bone marrow are myeloid cell reservoirs for the meninges and CNS parenchyma. Science 373, eabf7844 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Gautier, E. L. et al. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat. Immunol. 13, 1118–1128 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Gosselin, D. et al. Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell 159, 1327–1340 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Matcovitch-Natan, O. et al. Microglia development follows a stepwise program to regulate brain homeostasis. Science 353, aad8670 (2016).

    Article  PubMed  Google Scholar 

  69. Bennett, F. C. et al. A combination of ontogeny and CNS environment establishes microglial identity. Neuron 98, 1170–1183 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Buttgereit, A. et al. Sall1 is a transcriptional regulator defining microglia identity and function. Nat. Immunol. 17, 1397–1406 (2016).

    Article  CAS  PubMed  Google Scholar 

  71. Scott, C. L. et al. Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells. Nat. Commun. 7, 10321 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. van de Laar, L. et al. Yolk sac macrophages, fetal liver, and adult monocytes can colonize an empty niche and develop into functional tissue-resident macrophages. Immunity 44, 755–768 (2016).

    Article  PubMed  Google Scholar 

  73. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Lund, H. et al. Competitive repopulation of an empty microglial niche yields functionally distinct subsets of microglia-like cells. Nat. Commun. 9, 4845 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Shemer, A. et al. Engrafted parenchymal brain macrophages differ from microglia in transcriptome, chromatin landscape and response to challenge. Nat. Commun. 9, 5206 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Green, K. N., Crapser, J. D. & Hohsfield, L. A. To kill a microglia: a case for CSF1R inhibitors. Trends Immunol. 41, 771–784 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Masuda, T. et al. Novel Hexb-based tools for studying microglia in the CNS. Nat. Immunol. 21, 802–815 (2020).

    Article  CAS  PubMed  Google Scholar 

  78. Nicholson, A. M. et al. CSF1R mutations link POLD and HDLS as a single disease entity. Neurology 80, 1033–1040 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Oosterhof, N. et al. Homozygous mutations in CSF1R cause a pediatric-onset leukoencephalopathy and can result in congenital absence of microglia. Am. J. Hum. Genet. 104, 936–947 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Kana, V. et al. CSF-1 controls cerebellar microglia and is required for motor function and social interaction. J. Exp. Med. 216, 2265–2281 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Chitu, V., Gokhan, Ş., Nandi, S., Mehler, M. F. & Stanley, E. R. Emerging roles for CSF-1 receptor and its ligands in the nervous system. Trends Neurosci. 39, 378–393 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Abboud, S. L., Bunegin, M., Ghosh-Choudhury, N. & Woodruff, K. Analysis of the mouse CSF-1 gene promoter in a transgenic mouse model. J. Histochem. Cytochem. 51, 941–949 (2003).

    Article  CAS  PubMed  Google Scholar 

  83. Easley-Neal, C., Foreman, O., Sharma, N., Zarrin, A. A. & Weimer, R. M. CSF1R ligands IL-34 and CSF1 are differentially required for microglia development and maintenance in white and gray matter brain regions. Front. Immunol. 10, 2199 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Greter, M. et al. Stroma-derived interleukin-34 controls the development and maintenance of Langerhans cells and the maintenance of microglia. Immunity 37, 1050–1060 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Wang, Y. et al. IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia. Nat. Immunol. 13, 753–760 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Rojo, R. et al. Deletion of a Csf1r enhancer selectively impacts CSF1R expression and development of tissue macrophage populations. Nat. Commun. 10, 3215 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Butovsky, O. et al. Identification of a unique TGF-β-dependent molecular and functional signature in microglia. Nat. Neurosci. 17, 131–143 (2014). This paper established TGF-β as an important niche factor for microglial cell identity and function.

    Article  CAS  PubMed  Google Scholar 

  88. Zöller, T. et al. Silencing of TGFβ signalling in microglia results in impaired homeostasis. Nat. Commun. 9, 4011 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Robertson, I. B. & Rifkin, D. B. Regulation of the bioavailability of TGF-β and TGF-β-related proteins. Cold Spring Harb. Perspect. Biol. 8, a021907 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Wrana, J. L., Attisano, L., Wieser, R., Ventura, F. & Massagué, J. Mechanism of activation of the TGF-β receptor. Nature 370, 341–347 (1994).

    Article  CAS  PubMed  Google Scholar 

  91. Qin, Y. et al. A milieu molecule for TGF-β required for microglia function in the nervous system. Cell 174, 156–171 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Wong, K. et al. Mice deficient in NRROS show abnormal microglial development and neurological disorders. Nat. Immunol. 18, 633–641 (2017).

    Article  CAS  PubMed  Google Scholar 

  93. Arnold, T. D. et al. Impaired αVβ8 and TGFβ signaling lead to microglial dysmaturation and neuromotor dysfunction. J. Exp. Med. 216, 900–915 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Abutbul, S. et al. TGF-β signaling through SMAD2/3 induces the quiescent microglial phenotype within the CNS environment. Glia 60, 1160–1171 (2012).

    Article  PubMed  Google Scholar 

  95. Smith, C. et al. Biallelic mutations in NRROS cause an early onset lethal microgliopathy. Acta Neuropathol. 139, 947–951 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Otero, K. et al. Macrophage colony-stimulating factor induces the proliferation and survival of macrophages via a pathway involving DAP12 and β-catenin. Nat. Immunol. 10, 734–743 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Nataf, S. et al. Brain and bone damage in KARAP/DAP12 loss-of-function mice correlate with alterations in microglia and osteoclast lineages. Am. J. Pathol. 166, 275–286 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Erny, D. et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat. Neurosci. 18, 965–977 (2015). This study shows that the presence of microbiota is essential for microglia to acquire their adult phenotype and to be able to initiate proper immune reactions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Erny, D. et al. Microbiota-derived acetate enables the metabolic fitness of the brain innate immune system during health and disease. Cell Metab. 33, 2260–2276 (2021).

    Article  CAS  PubMed  Google Scholar 

  100. Mezö, C. et al. Different effects of constitutive and induced microbiota modulation on microglia in a mouse model of Alzheimer’s disease. Acta Neuropathol. Commun. 8, 119 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Mossad, O. et al. Gut microbiota drives age-related oxidative stress and mitochondrial damage in microglia via the metabolite N6-carboxymethyllysine. Nat. Neurosci. 25, 295–305 (2022).

    Article  CAS  PubMed  Google Scholar 

  102. Boehme, M. et al. Microbiota from young mice counteracts selective age-associated behavioral deficits. Nat. Aging 1, 666–676 (2021).

    Article  Google Scholar 

  103. Sankowski, R. et al. Commensal microbiota divergently affect myeloid subsets in the mammalian central nervous system during homeostasis and disease. EMBO J. 40, e108605 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Mossad, O. & Erny, D. The microbiota–microglia axis in central nervous system disorders. Brain Pathol. 30, 1159–1177 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Keshavarzian, A., Engen, P., Bonvegna, S. & Cilia, R. The gut microbiome in Parkinson’s disease: a culprit or a bystander? In Progress in Brain Research (eds Björklund, A. & Cenci, M. A.) Vol. 252, 357–450 (Elsevier, 2020).

  106. Sampson, T. R. et al. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell 167, 1469–1480 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Abdel-Haq, R. et al. A prebiotic diet modulates microglial states and motor deficits in α-synuclein overexpressing mice. eLife 11, e81453 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  108. 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).

    Article  CAS  PubMed  Google Scholar 

  109. De Vlaminck, K. et al. Differential plasticity and fate of brain-resident and recruited macrophages during the onset and resolution of neuroinflammation. Immunity 55, 2085–2102 (2022).

    Article  PubMed  Google Scholar 

  110. Ransohoff, R. M., Kivisäkk, P. & Kidd, G. Three or more routes for leukocyte migration into the central nervous system. Nat. Rev. Immunol. 3, 569–581 (2003).

    Article  CAS  PubMed  Google Scholar 

  111. Schulz, M. & Engelhardt, B. The circumventricular organs participate in the immunopathogenesis of experimental autoimmune encephalomyelitis. Cerebrospinal Fluid Res. 2, 8 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  112. Herisson, F. et al. Direct vascular channels connect skull bone marrow and the brain surface enabling myeloid cell migration. Nat. Neurosci. 21, 1209–1217 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Pulous, F. E. et al. Cerebrospinal fluid can exit into the skull bone marrow and instruct cranial hematopoiesis in mice with bacterial meningitis. Nat. Neurosci. 25, 567–576 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Mazzitelli, J. A. et al. Cerebrospinal fluid regulates skull bone marrow niches via direct access through dural channels. Nat. Neurosci. 25, 555–560 (2022). These two studies suggest that CSF can access the skull bone marrow niche, which allows CNS-derived factors to directly manipulate the local HSC pool.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Tay, T. L. et al. A new fate mapping system reveals context-dependent random or clonal expansion of microglia. Nat. Neurosci. 20, 793–803 (2017).

    Article  CAS  PubMed  Google Scholar 

  116. Wu, X., Saito, T., Saido, T. C., Barron, A. M. & Ruedl, C. Microglia and CD206+ border-associated mouse macrophages maintain their embryonic origin during Alzheimer’s disease. eLife 10, e71879 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Reed-Geaghan, E. G., Croxford, A. L., Becher, B. & Landreth, G. E. Plaque-associated myeloid cells derive from resident microglia in an Alzheimer’s disease model. J. Exp. Med. 217, e20191374 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  118. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Silvin, A. et al. Dual ontogeny of disease-associated microglia and disease inflammatory macrophages in aging and neurodegeneration. Immunity 55, 1448–1465 (2022).

    Article  CAS  PubMed  Google Scholar 

  120. Yan, P. et al. Peripheral monocyte-derived cells counter amyloid plaque pathogenesis in a mouse model of Alzheimer’s disease. J. Clin. Invest. 132, e152565 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. 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).

    Article  PubMed  Google Scholar 

  123. Amorim, A. et al. IFNγ and GM-CSF control complementary differentiation programs in the monocyte-to-phagocyte transition during neuroinflammation. Nat. Immunol. 23, 217–228 (2022).

    Article  CAS  PubMed  Google Scholar 

  124. Rua, R. et al. Infection drives meningeal engraftment by inflammatory monocytes that impairs CNS immunity. Nat. Immunol. 20, 407–419 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Hawkes, C. A. & McLaurin, J. Selective targeting of perivascular macrophages for clearance of β-amyloid in cerebral amyloid angiopathy. Proc. Natl Acad. Sci. USA 106, 1261–1266 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. El Khoury, J. et al. Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat. Med. 13, 432–438 (2007).

    Article  CAS  PubMed  Google Scholar 

  127. Michaud, J.-P., Bellavance, M.-A., Préfontaine, P. & Rivest, S. Real-time in vivo imaging reveals the ability of monocytes to clear vascular amyloid beta. Cell Rep. 5, 646–653 (2013).

    Article  CAS  PubMed  Google Scholar 

  128. Cui, J. et al. Inflammation of the embryonic choroid plexus barrier following maternal immune activation. Dev. Cell 55, 617–628 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Waisman, A., Ginhoux, F., Greter, M. & Bruttger, J. Homeostasis of microglia in the adult brain: review of novel microglia depletion systems. Trends Immunol. 36, 625–636 (2015).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Heppner, F. L. et al. Experimental autoimmune encephalomyelitis repressed by microglial paralysis. Nat. Med. 11, 146–152 (2005).

    Article  CAS  PubMed  Google Scholar 

  132. Rooijen, N. V. & Sanders, A. Liposome mediated depletion of macrophages: mechanism of action, preparation of liposomes and applications. J. Immunol. Methods 174, 83–93 (1994).

    Article  PubMed  Google Scholar 

  133. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Dagher, N. N. et al. Colony-stimulating factor 1 receptor inhibition prevents microglial plaque association and improves cognition in 3xTg-AD mice. J. Neuroinflammation 12, 139 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  135. Huang, Y. et al. Repopulated microglia are solely derived from the proliferation of residual microglia after acute depletion. Nat. Neurosci. 21, 530–540 (2018).

    Article  CAS  PubMed  Google Scholar 

  136. Zhan, L. et al. Proximal recolonization by self-renewing microglia re-establishes microglial homeostasis in the adult mouse brain. PLoS Biol. 17, e3000134 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  137. Hagemeyer, N. et al. Microglia contribute to normal myelinogenesis and to oligodendrocyte progenitor maintenance during adulthood. Acta Neuropathol. 134, 441–458 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Bruttger, J. et al. Genetic cell ablation reveals clusters of local self-renewing microglia in the mammalian central nervous system. Immunity 43, 92–106 (2015).

    Article  CAS  PubMed  Google Scholar 

  139. Hohsfield, L. A. et al. Effects of long-term and brain-wide colonization of peripheral bone marrow-derived myeloid cells in the CNS. J. Neuroinflammation 17, 279 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Shibuya, Y. et al. Treatment of a genetic brain disease by CNS-wide microglia replacement. Sci. Transl. Med. 14, eabl9945 (2022). In a proof-of-concept approach, this study provides evidence that microglia can be fully replaced by circulating progenitors through a combination of bone marrow transfer and depletion and to treat a detrimental brain disease in mice.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Xu, Z. et al. Efficient strategies for microglia replacement in the central nervous system. Cell Rep. 32, 108041 (2020).

    Article  CAS  PubMed  Google Scholar 

  142. Rubino, S. J. et al. Acute microglia ablation induces neurodegeneration in the somatosensory system. Nat. Commun. 9, 4578 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  143. Peng, J., Zou, Q., Chen, M.-J., Ma, C.-L. & Li, B.-M. Motor deficits seen in microglial ablation mice could be due to non-specific damage from high dose diphtheria toxin treatment. Nat. Commun. 13, 3874 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Willis, E. F. et al. Repopulating microglia promote brain repair in an IL-6-dependent manner. Cell 180, 833–846 (2020).

    Article  CAS  PubMed  Google Scholar 

  145. Chokr, S. M., Milinkeviciute, G., Jimenez, G. A., Abubakr, H. & Cramer, K. S. Long-term microglia depletion impairs synapse elimination and auditory brainstem function. Sci. Rep. 12, 18521 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

T.M. was supported by the AMED (JP20gm6310016 (PRIME), JP21wm0425001) and the JSPS (KAKENHI JP21H02752, JP21H00204, JP22H05062). M.P. is supported by the Sobek Foundation, the Ernst Jung Foundation, the German Research Foundation (SFB 992, SFB 1160, SFB 1479, TRR 167, TRR 359, Reinhart Koselleck grant, Gottfried Wilhelm Leibniz prize) and the Ministry of Science, Research and Arts, Baden-Wuerttemberg (Sonderlinie ‘Neuroinflammation’) and by the BMBF-funded competence network of multiple sclerosis (KKNMS). This study was supported by the German Research Foundation (DFG) under Germany’s Excellence Strategy (CIBSS, EXC-2189, project ID 390939984).

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Authors and Affiliations

  1. Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany

    Lukas Amann & Marco Prinz

  2. Division of Molecular Neuroimmunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

    Takahiro Masuda

  3. Center for Basics in NeuroModulation (NeuroModulBasics), Faculty of Medicine, University of Freiburg, Freiburg, Germany

    Marco Prinz

  4. Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany

    Marco Prinz

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Amann, L., Masuda, T. & Prinz, M. Mechanisms of myeloid cell entry to the healthy and diseased central nervous system. Nat Immunol 24, 393–407 (2023). https://doi.org/10.1038/s41590-022-01415-8

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