Skip to main content

Advertisement

Log in

Contributions of monocytes to nervous system disorders

  • Review
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Monocytes are a class of leukocytes derived from progenitors in the bone marrow and are prevalent in the blood stream. Although the main function of monocytes is to provide innate immune defenses against infection and injury, their contributions to the central nervous system (CNS) disorders are increasingly recognized. In this review article, we summarize the molecular and physiological properties of monocytes in relation to other myeloid cells. Primarily, we discuss how monocytes (or leukocytes) may affect neuronal function in diseases that are characterized by dysregulated innate immunity and cognitive dysfunction. Under these pathological conditions, monocytes and monocyte-derived cells (1) fail to remove neurotoxic products from CNS, (2) interact with astrocytes at the periphery-brain interfaces to alter synapse development and plasticity, or (3) infiltrate into the CNS to exacerbate neuroinflammation. Through these cellular mechanisms, we speculate that monocytes and other peripheral immune cells may affect brain functioning and contribute to behavioral and cognitive deficits. Better understanding of neuroimmune interactions will help the development of strategies to ameliorate neuronal and cognitive dysfunction associated with dysregulated innate immunity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. van Furth R, Cohn ZA (1968) The origin and kinetics of mononuclear phagocytes. J Exp Med 128(3):415–435

    Article  PubMed  PubMed Central  Google Scholar 

  2. Shi C, Pamer EG (2011) Monocyte recruitment during infection and inflammation. Nat Rev Immunol 11(11):762–774

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Brynskikh A et al (2008) Adaptive immunity affects learning behavior in mice. Brain Behav Immun 22(6):861–869

    Article  PubMed  CAS  Google Scholar 

  4. Derecki NC et al (2010) Regulation of learning and memory by meningeal immunity: a key role for IL-4. J Exp Med 207(5):1067–1080

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Derecki NC, Quinnies KM, Kipnis J (2011) Alternatively activated myeloid (M2) cells enhance cognitive function in immune compromised mice. Brain Behav Immun 25(3):379–385

    Article  PubMed  CAS  Google Scholar 

  6. Garre JM et al (2017) CX3CR1+ monocytes modulate learning and learning-dependent dendritic spine remodeling via TNF-alpha. Nat Med 23(6):714–722

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Geissmann F, Jung S, Littman DR (2003) Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19:71–82

    Article  PubMed  CAS  Google Scholar 

  8. Ginhoux F, Jung S (2014) Monocytes and macrophages: developmental pathways and tissue homeostasis. Nat Rev Immunol 14(6):392–404

    Article  PubMed  CAS  Google Scholar 

  9. Prinz M, Priller J (2017) The role of peripheral immune cells in the CNS in steady state and disease. Nat Neurosci 20(2):136–144

    Article  PubMed  CAS  Google Scholar 

  10. Auffray C et al (2007) Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science 317:666–670

    Article  PubMed  CAS  Google Scholar 

  11. Ajami B et al (2018) Single-cell mass cytometry reveals distinct populations of brain myeloid cells in mouse neuroinflammation and neurodegeneration models. Nat Neurosci 21(4):541–551

    Article  PubMed  CAS  Google Scholar 

  12. Ginhoux F et al (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330:841–845

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Gomez Perdiguero E et al (2015) Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 518:547–551

    Article  PubMed  CAS  Google Scholar 

  14. Alliot F et al (1991) Microglial progenitors with a high proliferative potential in the embryonic and adult mouse brain. Proc Natl Acad Sci U S A 88(4):1541–1545

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Alliot F, Godin I, Pessac B (1999) Microglia derive from progenitors, originating from the yolk sac, and which proliferate in the brain. Brain Res Dev Brain Res 117(2):145–152

    Article  PubMed  CAS  Google Scholar 

  16. Goldmann T et al (2016) Origin, fate and dynamics of macrophages at central nervous system interfaces. Nat Immunol 17(7):797–805

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Perdiguero EG, Geissmann F (2016) The development and maintenance of resident macrophages. Nat Immunol 17(1):2–8

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Tay TL, Mai D, Dautzenberg J, Fernández-Klett F, Lin G, Sagar, Datta M, Drougard A, Stempfl T, Ardura-Fabregat A, Staszewski O, Margineanu A, Sporbert A, Steinmetz LM, Pospisilik JA, Jung S, Priller J, Grün D, Ronneberger O, Prinz M (2017) A new fate mapping system reveals context-dependent random or clonal expansion ofmicroglia. Nat Neurosci 20:793–803

    Article  PubMed  CAS  Google Scholar 

  19. Fuger P et al (2017) Microglia turnover with aging and in an Alzheimer's model via long-term in vivo single-cell imaging. Nat Neurosci 20:1371–1376

    Article  PubMed  CAS  Google Scholar 

  20. Fogg DK et al (2006) A clonogenic bone marrow progenitor specific for macrophages and dendritic cells. Science 311(5757):83–87

    Article  PubMed  CAS  Google Scholar 

  21. Varol C et al (2007) Monocytes give rise to mucosal, but not splenic, conventional dendritic cells. J Exp Med 204(1):171–180

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Hettinger J et al (2013) Origin of monocytes and macrophages in a committed progenitor. Nat Immunol 14(8):821–830

    Article  PubMed  CAS  Google Scholar 

  23. Ziegler-Heitbrock L et al (2010) Nomenclature of monocytes and dendritic cells in blood. Blood 116(16):e74–e80

    Article  PubMed  CAS  Google Scholar 

  24. Cros J et al (2010) Human CD14dim monocytes patrol and sense nucleic acids and viruses via TLR7 and TLR8 receptors. Immunity 33(3):375–386

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Ransohoff RM, Engelhardt B (2012) The anatomical and cellular basis of immune surveillance in the central nervous system. Nat Rev Immunol 12(9):623–635

    Article  PubMed  CAS  Google Scholar 

  26. Becher B et al (2014) High-dimensional analysis of the murine myeloid cell system. Nat Immunol 15(12):1181–1189

    Article  PubMed  CAS  Google Scholar 

  27. Mildner A et al (2017) Genomic characterization of murine monocytes reveals C/EBPβ transcription factor dependence of Ly6C(−) cells. Immunity 46:849–862

    Article  PubMed  CAS  Google Scholar 

  28. Mrdjen D et al (2018) High-dimensional single-cell mapping of central nervous system immune cells reveals distinct myeloid subsets in health, aging, and disease. Immunity 48(3):599

    Article  PubMed  CAS  Google Scholar 

  29. Jung S et al (2000) Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol Cell Biol 20(11):4106–4114

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Goldmann T et al (2013) A new type of microglia gene targeting shows TAK1 to be pivotal in CNS autoimmune inflammation. Nat Neurosci 16(11):1618–1626

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  32. Patel AA et al (2017) The fate and lifespan of human monocyte subsets in steady state and systemic inflammation. J Exp Med 214(7):1913–1923

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Jakubzick C et al (2008) Blood monocyte subsets differentially give rise to CD103+ and CD103- pulmonary dendritic cell populations. J Immunol 180(5):3019–3027

    Article  PubMed  CAS  Google Scholar 

  34. Hanoun M et al (2015) Neural regulation of hematopoiesis, inflammation, and cancer. Neuron 86(2):360–373

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Wilson A, Laurenti E, Trumpp A (2009) Balancing dormant and self-renewing hematopoietic stem cells. Curr Opin Genet Dev 19(5):461–468

    Article  PubMed  CAS  Google Scholar 

  36. Reader BF et al (2015) Peripheral and central effects of repeated social defeat stress: monocyte trafficking, microglial activation, and anxiety. Neuroscience 289:429–442

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Borovikova LV et al (2000) Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405(6785):458–462

    Article  PubMed  CAS  Google Scholar 

  38. Maestroni GJ et al (1998) Neural and endogenous catecholamines in the bone marrow. Circadian association of norepinephrine with hematopoiesis? Exp Hematol 26(12):1172–1177

    PubMed  CAS  Google Scholar 

  39. Mendez-Ferrer S et al (2008) Haematopoietic stem cell release is regulated by circadian oscillations. Nature 452(7186):442–447

    Article  PubMed  CAS  Google Scholar 

  40. Nguyen KD et al (2013) Circadian gene Bmal1 regulates diurnal oscillations of Ly6C(hi) inflammatory monocytes. Science 341(6153):1483–1488

    Article  PubMed  CAS  Google Scholar 

  41. Zuroff L et al (2017) Clearance of cerebral Abeta in Alzheimer's disease: reassessing the role of microglia and monocytes. Cell Mol Life Sci 74(12):2167–2201

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Prokop S et al (2015) Impact of peripheral myeloid cells on amyloid-beta pathology in Alzheimer's disease-like mice. J Exp Med 212(11):1811–1818

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Bruttger J et al (2015) Genetic cell ablation reveals clusters of local self-renewing microglia in the mammalian central nervous system. Immunity 43(1):92–106

    Article  PubMed  CAS  Google Scholar 

  44. Keren-Shaul H et al (2017) A unique microglia type associated with restricting development of Alzheimer's disease. Cell 169(7):1276–1290 e17

    Article  PubMed  CAS  Google Scholar 

  45. El Khoury J et al (2007) Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat Med 13(4):432–438

    Article  PubMed  CAS  Google Scholar 

  46. Koronyo Y et al (2015) Therapeutic effects of glatiramer acetate and grafted CD115(+) monocytes in a mouse model of Alzheimer's disease. Brain 138(Pt 8):2399–2422

    Article  PubMed  PubMed Central  Google Scholar 

  47. Koronyo-Hamaoui M et al (2009) Attenuation of AD-like neuropathology by harnessing peripheral immune cells: local elevation of IL-10 and MMP-9. J Neurochem 111(6):1409–1424

    Article  PubMed  CAS  Google Scholar 

  48. Lebson L et al (2010) Trafficking CD11b-positive blood cells deliver therapeutic genes to the brain of amyloid-depositing transgenic mice. J Neurosci 30(29):9651–9658

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  50. Michaud JP et al (2013) Real-time in vivo imaging reveals the ability of monocytes to clear vascular amyloid beta. Cell Rep 5(3):646–653

    Article  PubMed  CAS  Google Scholar 

  51. Bradshaw EM et al (2013) CD33 Alzheimer's disease locus: altered monocyte function and amyloid biology. Nat Neurosci 16(7):848–850

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Iliff JJ et al (2012) A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med 4:147ra111

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Aspelund A et al (2015) A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J Exp Med 212(7):991–999

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Louveau A et al (2015) Structural and functional features of central nervous system lymphatic vessels. Nature 523(7560):337–341

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Peng W et al (2016) Suppression of glymphatic fluid transport in a mouse model of Alzheimer's disease. Neurobiol Dis 93:215–225

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Mostafavi S et al (2018) A molecular network of the aging human brain provides insights into the pathology and cognitive decline of Alzheimer's disease. Nat Neurosci 21(6):811–819

    Article  PubMed  CAS  Google Scholar 

  57. Shechter R et al (2013) Recruitment of beneficial M2 macrophages to injured spinal cord is orchestrated by remote brain choroid plexus. Immunity 38(3):555–569

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Kigerl KA et al (2009) Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J Neurosci 29(43):13435–13444

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Donnelly DJ et al (2011) Deficient CX3CR1 signaling promotes recovery after mouse spinal cord injury by limiting the recruitment and activation of Ly6Clo/iNOS+ macrophages. J Neurosci 31(27):9910–9922

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Makinde HM et al (2017) Nonclassical monocytes mediate secondary injury, neurocognitive outcome, and neutrophil infiltration after traumatic brain injury. J Immunol 199(10):3583–3591

    Article  PubMed  CAS  Google Scholar 

  61. Popovich PG et al (1999) Depletion of hematogenous macrophages promotes partial hindlimb recovery and neuroanatomical repair after experimental spinal cord injury. Exp Neurol 158(2):351–365

    Article  PubMed  CAS  Google Scholar 

  62. Kroner A et al (2014) TNF and increased intracellular iron alter macrophage polarization to a detrimental M1 phenotype in the injured spinal cord. Neuron 83(5):1098–1116

    Article  PubMed  CAS  Google Scholar 

  63. Shechter R et al (2009) Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice. PLoS Med 6(7):e1000113

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Wohleb ES et al (2013) Stress-induced recruitment of bone marrow-derived monocytes to the brain promotes anxiety-like behavior. J Neurosci 33(34):13820–13833

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. McKim DB et al (2016) Sympathetic release of splenic monocytes promotes recurring anxiety following repeated social defeat. Biol Psychiatry 79(10):803–813

    Article  PubMed  CAS  Google Scholar 

  66. Hodes GE et al (2014) Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress. Proc Natl Acad Sci U S A 111(45):16136–16141

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Mota R et al (2013) Interleukin-1beta is associated with depressive episode in major depression but not in bipolar disorder. J Psychiatr Res 47(12):2011–2014

    Article  PubMed  Google Scholar 

  68. Meyer U (2014) Prenatal poly(i:C) exposure and other developmental immune activation models in rodent systems. Biol Psychiatry 75(4):307–315

    Article  PubMed  CAS  Google Scholar 

  69. Giovanoli S et al (2013) Stress in puberty unmasks latent neuropathological consequences of prenatal immune activation in mice. Science 339(6123):1095–1099

    Article  PubMed  CAS  Google Scholar 

  70. Choi GB et al (2016) The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science 351(6276):933–939

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Kim S et al (2017) Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring. Nature 549(7673):528–532

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Yang D et al (2014) Blocking lymphocyte trafficking with FTY720 prevents inflammation-sensitized hypoxic-ischemic brain injury in newborns. J Neurosci 34(49):16467–16481

    Article  PubMed  PubMed Central  Google Scholar 

  73. Lombardi LM, Baker SA, Zoghbi HY (2015) MECP2 disorders: from the clinic to mice and back. J Clin Invest 125(8):2914–2923

    Article  PubMed  PubMed Central  Google Scholar 

  74. Yang T et al (2012) Overexpression of methyl-CpG binding protein 2 impairs T(H)1 responses. Sci Transl Med 4(163):163ra158

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Cronk JC et al (2015) Methyl-CpG binding protein 2 regulates microglia and macrophage gene expression in response to inflammatory stimuli. Immunity 42(4):679–691

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Schafer DP et al (2016) Microglia contribute to circuit defects in Mecp2 null mice independent of microglia-specific loss of Mecp2 expression. Elife 5

  77. Hong S et al (2016) Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352(6286):712–716

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Filiano AJ et al (2016) Unexpected role of interferon-gamma in regulating neuronal connectivity and social behaviour. Nature 535(7612):425–429

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Klein RS, Garber C, Howard N (2017) Infectious immunity in the central nervous system and brain function. Nat Immunol 18(2):132–141

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Brot MD et al (1997) Deficits in discriminated learning remain despite clearance of long-term persistent viral infection in mice. J Neuro-Oncol 3(4):265–273

    CAS  Google Scholar 

  81. Kim JV et al (2009) Myelomonocytic cell recruitment causes fatal CNS vascular injury during acute viral meningitis. Nature 457(7226):191–195

    Article  PubMed  CAS  Google Scholar 

  82. Mogensen TH (2009) Pathogen recognition and inflammatory signaling in innate immune defenses. Clin Microbiol Rev 22(2):240–273 Table of Contents

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Wolf Y et al (2017) Autonomous TNF is critical for in vivo monocyte survival in steady state and inflammation. J Exp Med 214(4):905–917

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. D'Mello C et al (2013) P-selectin-mediated monocyte-cerebral endothelium adhesive interactions link peripheral organ inflammation to sickness behaviors. J Neurosci 33(37):14878–14888

    Article  PubMed  CAS  Google Scholar 

  85. Venkatesh D et al (2013) Endothelial TNF receptor 2 induces IRF1 transcription factor-dependent interferon-beta autocrine signaling to promote monocyte recruitment. Immunity 38(5):1025–1037

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Blank T et al (2016) Brain endothelial- and epithelial-specific interferon receptor chain 1 drives virus-induced sickness behavior and cognitive impairment. Immunity 44(4):901–912

    Article  PubMed  CAS  Google Scholar 

  87. Vasek MJ et al (2016) A complement-microglial axis drives synapse loss during virus-induced memory impairment. Nature 534(7608):538–543

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Araque A et al (2014) Gliotransmitters travel in time and space. Neuron 81(4):728–739

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Eroglu C, Barres BA (2010) Regulation of synaptic connectivity by glia. Nature 468(7321):223–231

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Allen NJ et al (2012) Astrocyte glypicans 4 and 6 promote formation of excitatory synapses via GluA1 AMPA receptors. Nature 486(7403):410–414

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Allen NJ, Eroglu C (2017) Cell biology of astrocyte-synapse interactions. Neuron 96(3):697–708

    Article  PubMed  CAS  Google Scholar 

  92. Tran MD, Neary JT (2006) Purinergic signaling induces thrombospondin-1 expression in astrocytes. Proc Natl Acad Sci U S A 103(24):9321–9326

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Santello M, Bezzi P, Volterra A (2011) TNFalpha controls glutamatergic gliotransmission in the hippocampal dentate gyrus. Neuron 69(5):988–1001

    Article  PubMed  CAS  Google Scholar 

  94. Habbas S et al (2015) Neuroinflammatory TNFα impairs memory via astrocyte signaling. Cell 163:1730–1741

    Article  PubMed  CAS  Google Scholar 

  95. Garber C et al (2018) Astrocytes decrease adult neurogenesis during virus-induced memory dysfunction via IL-1. Nat Immunol 19(2):151–161

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Garre JM, Bennett MVL (2009) Gap junctions as electrical synapses. (The sticky synapse- Cell Adhesion Molecules and their role in Synapse Formation and Maintenance ): p. Chapter 21. Springer, New York

  97. Rouach N et al (2008) Astroglial metabolic networks sustain hippocampal synaptic transmission. Science 322(5907):1551–1555

    Article  PubMed  CAS  Google Scholar 

  98. Retamal MA et al (2007) Cx43 hemichannels and gap junction channels in astrocytes are regulated oppositely by proinflammatory cytokines released from activated microglia. J Neurosci 27(50):13781–13792

    Article  PubMed  CAS  Google Scholar 

  99. Garre JM et al (2010) FGF-1 induces ATP release from spinal astrocytes in culture and opens pannexin and connexin hemichannels. Proc Natl Acad Sci U S A 107(52):22659–22664

    Article  PubMed  PubMed Central  Google Scholar 

  100. De Bock M et al (2016) Into rather unexplored terrain-transcellular transport across the blood-brain barrier. Glia 64(7):1097–1123

    Article  PubMed  Google Scholar 

Download references

Funding

This study was supported by funding from the NIH (R01 GM107469 and R21 NS106469 to G.Y.).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Juan Mauricio Garré or Guang Yang.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Garré, J.M., Yang, G. Contributions of monocytes to nervous system disorders. J Mol Med 96, 873–883 (2018). https://doi.org/10.1007/s00109-018-1672-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-018-1672-3

Keywords

Navigation