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Central nervous system myeloid cells as drug targets: current status and translational challenges

Nature Reviews Drug Discovery volume 15, pages 110–124 (2016)Cite this article

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Key Points

  • Brain myeloid cells are a diverse group of mononuclear cells that mediate the local immune response during development, health and brain diseases. They consist of endogenous microglia, CNS-resident macrophages and monocytes that infiltrate the diseased CNS, each of them having specific disease-related functions.

  • Mutations in microglial-related genes can have a significant impact on the functions of these cells and are linked to various disorders. Primary microgliopathies are usually caused by a single gene mutation, whereby the lack of a distinct microglial-associated gene results in microglia dysfunction accompanied by neural damage.

  • In secondary myeloid cell brain disorders, myeloid cells undergo a shift towards a disease-specific phenotype that potentially contributes to the chronicity of these diseases.

  • There are various lines of evidence showing significant differences in myeloid cell function between mice and humans. From a drug discovery perspective, it is crucial to understand whether findings in mice also apply to brain myeloid cells in humans.

  • Brain myeloid cells are increasingly being recognized as promising potential targets for the treatment of CNS disorders. Several pharmaceutical drug development programmes targeting brain myeloid cells have been initiated, with more anticipated in the near future.

Abstract

Myeloid cells of the central nervous system (CNS), which include parenchymal microglia, macrophages at CNS interfaces and monocytes recruited from the circulation during disease, are increasingly being recognized as targets for therapeutic intervention in neurological and psychiatric diseases. The origin of these cells in the immune system distinguishes them from ectodermal neurons and other glia and endows them with potential drug targets distinct from classical CNS target groups. However, despite the identification of several promising therapeutic approaches and molecular targets, no agents directly targeting these cells are currently available. Here, we assess strategies for targeting CNS myeloid cells and address key issues associated with their translation into the clinic.

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Figure 1: Myeloid cells of the diseased brain.

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References

  1. Prinz, M. & Priller, J. Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nat. Rev. Neurosci. 15, 300–312 (2014).

    Article  CAS  PubMed  Google Scholar 

  2. 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 

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

    Article  CAS  PubMed  Google Scholar 

  4. 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). A landmark paper providing convincing evidence of the diversity of the myeloid cell system, including some brain myeloid cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. 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 

  6. Lavin, Y. et al. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 159, 1312–1326 (2014). References 5 and 6 both show independently that myeloid cell diversity is shaped by the environment, which is reflected by changes in the epigenome.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Butovsky, O. et al. Identification of a unique TGF-β-dependent molecular and functional signature in microglia. Nat. Neurosci. 17, 131–143 (2014). The paper identifies various microglia-specific genes.

    Article  CAS  PubMed  Google Scholar 

  8. Erny, D. et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat. Neurosci. 18, 965–977 (2015). A landmark paper showing that the gut microbiota is important for proper microglia function.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hickman, S. E. et al. The microglial sensome revealed by direct RNA sequencing. Nat. Neurosci. 16, 1896–1905 (2013). The first thorough analysis of the receptor profile of mature microglia from the adult brain.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  11. Nimmerjahn, A., Kirchhoff, F. & Helmchen, F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 1314–1318 (2005). One of the most influential papers on microglia of the past decade, this study provides initial proof that microglial processes constantly move and survey their environment.

    Article  CAS  PubMed  Google Scholar 

  12. Tremblay, M.-È., Lowery, R. L. & Majewska, A. K. Microglial interactions with synapses are modulated by visual experience. PLoS Biol. 8, e1000527 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wake, H., Moorhouse, A. J., Jinno, S., Kohsaka, S. & Nabekura, J. Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J. Neurosci. 29, 3974–3980 (2009). References 12 and 13 are landmark papers showing convincingly that microglia have brief contacts with active synapses, indicating their role in modulating synaptic activity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Roumier, A. et al. Impaired synaptic function in the microglial KARAP/DAP12-deficient mouse. J. Neurosci. 24, 11421–11428 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zhan, Y. et al. Deficient neuron–microglia signaling results in impaired functional brain connectivity and social behavior. Nat. Neurosci. 17, 400–406 (2014).

    Article  CAS  PubMed  Google Scholar 

  16. Marín-Teva, J. L. et al. Microglia promote the death of developing Purkinje cells. Neuron 41, 535–547 (2004).

    Article  PubMed  Google Scholar 

  17. Ueno, M. et al. Layer V cortical neurons require microglial support for survival during postnatal development. Nat. Neurosci. 16, 543–551 (2013).

    Article  CAS  PubMed  Google Scholar 

  18. Dijkstra, C. D., Döpp, E. A., Joling, P. & Kraal, G. The heterogeneity of mononuclear phagocytes in lymphoid organs: distinct macrophage subpopulations in the rat recognized by monoclonal antibodies ED1, ED2 and ED3. Immunology 54, 589–599 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Serrats, J. et al. Dual roles for perivascular macrophages in immune-to-brain signaling. Neuron 65, 94–106 (2010). One of the few papers that thoroughly addresses the function of perivascular macrophages.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Auffray, C. et al. CX3CR1+ CD115+ CD135+ common macrophage/DC precursors and the role of CX3CR1 in their response to inflammation. J. Exp. Med. 206, 595–606 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Geissmann, F., Gordon, S., Hume, D. A., Mowat, A. M. & Randolph, G. J. Unravelling mononuclear phagocyte heterogeneity. Nat. Rev. Immunol. 10, 453–460 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Mizutani, M. et al. The fractalkine receptor but not CCR2 is present on microglia from embryonic development throughout adulthood. J. Immunol. 188, 29–36 (2012).

    Article  CAS  PubMed  Google Scholar 

  23. Saederup, N. et al. Selective chemokine receptor usage by central nervous system myeloid cells in CCR2-red fluorescent protein knock-in mice. PLoS ONE 5, e13693 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kierdorf, K. et al. Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nat. Neurosci. 16, 273–280 (2013). A complete description of the microglia progenitor and important transcription factors in microglia differentiation.

    Article  CAS  PubMed  Google Scholar 

  26. 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 

  27. 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). A landmark paper showing that there is no regular exchange of the microglia population from outside the brain.

    Article  CAS  PubMed  Google Scholar 

  28. 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). This study describes how local conditioning is required for bone marrow cell engraftment into the CNS.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  31. Yona, S. et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38, 79–91 (2013). References 30 and 31 are the first description of microglia-specific Cre lines.

    Article  CAS  PubMed  Google Scholar 

  32. Lambertsen, K. L., Biber, K. & Finsen, B. Inflammatory cytokines in experimental and human stroke. J. Cereb. Blood Flow Metab. 32, 1677–1698 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Prinz, M., Priller, J., Sisodia, S. S. & Ransohoff, R. M. Heterogeneity of CNS myeloid cells and their roles in neurodegeneration. Nat. Neurosci. 14, 1227–1235 (2011).

    Article  CAS  PubMed  Google Scholar 

  34. Kreutzberg, G. W. Microglia: a sensor for pathological events in the CNS. Trends Neurosci. 19, 312–318 (1996).

    Article  CAS  PubMed  Google Scholar 

  35. Streit, W. J., Walter, S. A. & Pennell, N. A. Reactive microgliosis. Prog. Neurobiol. 57, 563–581 (1999).

    Article  CAS  PubMed  Google Scholar 

  36. Tremblay, M.-È. et al. The role of microglia in the healthy brain. J. Neurosci. 31, 16064–16069 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Sierra, A., Tremblay, M.-È. & Wake, H. Never-resting microglia: physiological roles in the healthy brain and pathological implications. Front. Cell. Neurosci. 8, 240 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Rademakers, R. et al. Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. Nat. Genet. 44, 200–205 (2012).

    Article  CAS  Google Scholar 

  39. Goldmann, T. et al. USP18 lack in microglia causes destructive interferonopathy of the mouse brain. EMBO J. 34, 1612–1629 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Chen, S.-K. et al. Hematopoietic origin of pathological grooming in Hoxb8 mutant mice. Cell 141, 775–785 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 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. 4, e124 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Bradshaw, E. M. et al. CD33 Alzheimer's disease locus: altered monocyte function and amyloid biology. Nat. Neurosci. 16, 848–850 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Griciuc, A. et al. Alzheimer's disease risk gene CD33 inhibits microglial uptake of amyloid β. Neuron 78, 631–643 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Guerreiro, R. J. et al. Using exome sequencing to reveal mutations in TREM2 presenting as a frontotemporal dementia-like syndrome without bone involvement. JAMA Neurol. 70, 78–84 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  45. De Jager, P. L. et al. Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci. Nat. Genet. 41, 776–782 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. International Multiple Sclerosis Genetics Consortium. The genetic association of variants in CD6, TNFRSF1A and IRF8 to multiple sclerosis: a multicenter case–control study. PLoS ONE 6, e18813 (2011).

  47. Djukic, M. et al. Circulating monocytes engraft in the brain, differentiate into microglia and contribute to the pathology following meningitis in mice. Brain J. Neurol. 129, 2394–2403 (2006).

    Article  Google Scholar 

  48. Malm, T. M. et al. Bone-marrow-derived cells contribute to the recruitment of microglial cells in response to β-amyloid deposition in APP/PS1 double transgenic Alzheimer mice. Neurobiol. Dis. 18, 134–142 (2005).

    Article  CAS  PubMed  Google Scholar 

  49. Priller, J. et al. Early and rapid engraftment of bone marrow-derived microglia in scrapie. J. Neurosci. 26, 11753–11762 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Solomon, J. N. et al. Origin and distribution of bone marrow-derived cells in the central nervous system in a mouse model of amyotrophic lateral sclerosis. Glia 53, 744–753 (2006).

    Article  PubMed  Google Scholar 

  51. 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 

  52. Biffi, A. et al. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science 341, 1233158 (2013).

    Article  CAS  PubMed  Google Scholar 

  53. Cartier, N. et al. Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science 326, 818–823 (2009).

    Article  CAS  PubMed  Google Scholar 

  54. Kierdorf, K., Katzmarski, N., Haas, C. A. & Prinz, M. Bone marrow cell recruitment to the brain in the absence of irradiation or parabiosis bias. PLoS ONE 8, e58544 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Biber, K., Owens, T. & Boddeke, E. What is microglia neurotoxicity (not)? Glia 62, 841–854 (2014).

    Article  PubMed  Google Scholar 

  56. Hellwig, S., Heinrich, A. & Biber, K. The brain's best friend: microglial neurotoxicity revisited. Front. Cell. Neurosci. 7, 71 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Sierra, A. et al. Surveillance, phagocytosis, and inflammation: how never-resting microglia influence adult hippocampal neurogenesis. Neural Plast. 2014, 610343 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Sierra, A., Abiega, O., Shahraz, A. & Neumann, H. Janus-faced microglia: beneficial and detrimental consequences of microglial phagocytosis. Front. Cell. Neurosci. 7, 6 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Block, M. L., Zecca, L. & Hong, J.-S. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat. Rev. Neurosci. 8, 57–69 (2007).

    Article  CAS  PubMed  Google Scholar 

  60. Benveniste, E. N. Role of macrophages/microglia in multiple sclerosis and experimental allergic encephalomyelitis. J. Mol. Med. Berl. Ger. 75, 165–173 (1997).

    Article  CAS  Google Scholar 

  61. Goldmann, T. & Prinz, M. Role of microglia in CNS autoimmunity. Clin. Dev. Immunol. 2013, 208093 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Ellrichmann, G. et al. Constitutive activity of NF-κB in myeloid cells drives pathogenicity of monocytes and macrophages during autoimmune neuroinflammation. J. Neuroinflamm. 9, 15 (2012).

    Article  CAS  Google Scholar 

  63. Vainchtein, I. D. et al. In acute experimental autoimmune encephalomyelitis, infiltrating macrophages are immune activated, whereas microglia remain immune suppressed. Glia 62, 1724–1735 (2014).

    Article  CAS  PubMed  Google Scholar 

  64. Yamasaki, R. et al. Differential roles of microglia and monocytes in the inflamed central nervous system. J. Exp. Med. 211, 1533–1549 (2014). References 63 and 64 provide evidence for the different roles of microglia versus peripheral monocytes in the EAE brain.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Evans, T. A. et al. High-resolution intravital imaging reveals that blood-derived macrophages but not resident microglia facilitate secondary axonal dieback in traumatic spinal cord injury. Exp. Neurol. 254, 109–120 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Olah, M. et al. Identification of a microglia phenotype supportive of remyelination. Glia 60, 306–321 (2012).

    Article  PubMed  Google Scholar 

  67. Lambertsen, K. L. et al. Microglia protect neurons against ischemia by synthesis of tumor necrosis factor. J. Neurosci. 29, 1319–1330 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Chen, Z. & Trapp, B. D. Microglia and neuroprotection. J. Neurochem. http://dx.doi.org/10.1111/jnc.13062 (2015).

  69. Mosher, K. I. & Wyss-Coray, T. Microglial dysfunction in brain aging and Alzheimer's disease. Biochem. Pharmacol. 88, 594–604 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Coull, J. A. M. et al. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438, 1017–1021 (2005).

    Article  CAS  PubMed  Google Scholar 

  71. Inoue, K. & Tsuda, M. P2X4 receptors of microglia in neuropathic pain. CNS Neurol. Disord. Drug Targets 11, 699–704 (2012).

    Article  CAS  PubMed  Google Scholar 

  72. Butovsky, O. et al. Targeting miR-155 restores abnormal microglia and attenuates disease in SOD1 mice. Ann. Neurol. 77, 75–99 (2015).

    Article  CAS  PubMed  Google Scholar 

  73. Moore, C. S. et al. P2Y12 expression and function in alternatively activated human microglia. Neurol. Neuroimmunol. Neuroinflamm. 2, e80 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Verheijden, S. et al. Identification of a chronic non-neurodegenerative microglia activation state in a mouse model of peroxisomal β-oxidation deficiency. Glia 63, 1606–1620 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Getts, D. R. Editorial to special issue: monocytes in homeostasis and disease. Cell. Immunol. 291, 1–2 (2014).

    Article  CAS  PubMed  Google Scholar 

  76. Serbina, N. V. & Pamer, E. G. Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nat. Immunol. 7, 311–317 (2006).

    Article  CAS  PubMed  Google Scholar 

  77. 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 

  78. Getts, D. R. et al. Therapeutic inflammatory monocyte modulation using immune-modifying microparticles. Sci. Transl. Med. 6, 219ra7 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Schwartz, M. & Baruch, K. The resolution of neuroinflammation in neurodegeneration: leukocyte recruitment via the choroid plexus. EMBO J. 33, 7–22 (2014).

    Article  CAS  PubMed  Google Scholar 

  80. 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 

  81. Hickey, W. F., Ueno, K., Hiserodt, J. C. & Schmidt, R. E. Exogenously-induced, natural killer cell-mediated neuronal killing: a novel pathogenetic mechanism. J. Exp. Med. 176, 811–817 (1992).

    Article  CAS  PubMed  Google Scholar 

  82. Unger, E. R. et al. Male donor-derived cells in the brains of female sex-mismatched bone marrow transplant recipients: a Y-chromosome specific in situ hybridization study. J. Neuropathol. Exp. Neurol. 52, 460–470 (1993).

    Article  CAS  PubMed  Google Scholar 

  83. 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). A landmark paper showing the potential of CSF1R antagonists to deplete microglia in vivo.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Pyonteck, S. M. et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat. Med. 19, 1264–1272 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Steinman, L. Multiple sclerosis: a coordinated immunological attack against myelin in the central nervous system. Cell 85, 299–302 (1996).

    Article  CAS  PubMed  Google Scholar 

  86. Lutz, S. E. et al. Contribution of pannexin1 to experimental autoimmune encephalomyelitis. PLoS ONE 8, e66657 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Matute, C. et al. P2X7 receptor blockade prevents ATP excitotoxicity in oligodendrocytes and ameliorates experimental autoimmune encephalomyelitis. J. Neurosci. 27, 9525–9533 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Chen, L. & Brosnan, C. F. Exacerbation of experimental autoimmune encephalomyelitis in P2X7R−/− mice: evidence for loss of apoptotic activity in lymphocytes. J. Immunol. 176, 3115–3126 (2006).

    Article  CAS  PubMed  Google Scholar 

  89. Sharp, A. J. et al. P2X7 deficiency suppresses development of experimental autoimmune encephalomyelitis. J. Neuroinflamm. 5, 33 (2008).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  91. Moreno, M. et al. Conditional ablation of astroglial CCL2 suppresses CNS accumulation of M1 macrophages and preserves axons in mice with MOG peptide EAE. J. Neurosci. 34, 8175–8185 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Inagaki-Ohara, K., Kondo, T., Ito, M. & Yoshimura, A. SOCS, inflammation, and cancer. JAKSTAT 2, e24053 (2013).

    PubMed  PubMed Central  Google Scholar 

  93. Qin, H. et al. Signal transducer and activator of transcription-3/suppressor of cytokine signaling-3 (STAT3/SOCS3) axis in myeloid cells regulates neuroinflammation. Proc. Natl Acad. Sci. USA 109, 5004–5009 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Ponomarev, E. D., Veremeyko, T., Barteneva, N., Krichevsky, A. M. & Weiner, H. L. MicroRNA-124 promotes microglia quiescence and suppresses EAE by deactivating macrophages via the C/EBP-α–PU.1 pathway. Nat. Med. 17, 64–70 (2011). The first paper indicating that miRNAs are potential drug targets in brain myeloid cells.

    Article  CAS  PubMed  Google Scholar 

  95. Moore, C. S. et al. miR-155 as a multiple sclerosis-relevant regulator of myeloid cell polarization. Ann. Neurol. 74, 709–720 (2013).

    Article  CAS  PubMed  Google Scholar 

  96. Murugaiyan, G., Beynon, V., Mittal, A., Joller, N. & Weiner, H. L. Silencing microRNA-155 ameliorates experimental autoimmune encephalomyelitis. J. Immunol. 187, 2213–2221 (2011).

    Article  CAS  PubMed  Google Scholar 

  97. Mc Guire, C., Prinz, M., Beyaert, R. & van Loo, G. Nuclear factor kappa B (NF-κB) in multiple sclerosis pathology. Trends Mol. Med. 19, 604–613 (2013).

    Article  CAS  PubMed  Google Scholar 

  98. Malik, M. et al. CD33 Alzheimer's risk-altering polymorphism, CD33 expression, and exon 2 splicing. J. Neurosci. 33, 13320–13325 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Bard, F. et al. Peripherally administered antibodies against amyloidβ-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat. Med. 6, 916–919 (2000).

    Article  CAS  PubMed  Google Scholar 

  100. Janus, C. et al. Aβ peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease. Nature 408, 979–982 (2000).

    Article  CAS  PubMed  Google Scholar 

  101. Adolfsson, O. et al. An effector-reduced anti-β-amyloid (Aβ) antibody with unique Aβ binding properties promotes neuroprotection and glial engulfment of Aβ. J. Neurosci. 32, 9677–9689 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Kleinberger, G. et al. TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Sci. Transl. Med. 6, 243ra86 (2014).

    Article  CAS  PubMed  Google Scholar 

  103. Jiang, T. et al. Upregulation of TREM2 ameliorates neuropathology and rescues spatial cognitive impairment in a transgenic mouse model of Alzheimer's disease. Neuropsychopharmacology 39, 2949–2962 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Jay, T. R. et al. TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer's disease mouse models. J. Exp. Med. 212, 287–295 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Wang, Y. et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model. Cell 160, 1061–1071 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Saresella, M. et al. A complex proinflammatory role for peripheral monocytes in Alzheimer's disease. J. Alzheimers Dis. 38, 403–413 (2014).

    Article  CAS  PubMed  Google Scholar 

  107. Naert, G. & Rivest, S. A deficiency in CCR2+ monocytes: the hidden side of Alzheimer's disease. J. Mol. Cell. Biol. 5, 284–293 (2013).

    Article  CAS  PubMed  Google Scholar 

  108. Wolf, Y., Yona, S., Kim, K.-W. & Jung, S. Microglia, seen from the CX3CR1 angle. Front. Cell. Neurosci. 7, 26 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Lee, S. et al. CX3CR1 deficiency alters microglial activation and reduces beta-amyloid deposition in two Alzheimer's disease mouse models. Am. J. Pathol. 177, 2549–2562 (2010). This paper was the first to support the role of CX 3 CR1 as a drug target in Alzheimer disease.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Liu, Z., Condello, C., Schain, A., Harb, R. & Grutzendler, J. CX3CR1 in microglia regulates brain amyloid deposition through selective protofibrillar amyloid-β phagocytosis. J. Neurosci. 30, 17091–17101 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. McLarnon, J. G., Ryu, J. K., Walker, D. G. & Choi, H. B. Upregulated expression of purinergic P2X7 receptor in Alzheimer disease and amyloid-beta peptide-treated microglia and in peptide-injected rat hippocampus. J. Neuropathol. Exp. Neurol. 65, 1090–1097 (2006).

    Article  CAS  PubMed  Google Scholar 

  114. Parvathenani, L. K. et al. P2X7 mediates superoxide production in primary microglia and is up-regulated in a transgenic mouse model of Alzheimer's disease. J. Biol. Chem. 278, 13309–13317 (2003).

    Article  CAS  PubMed  Google Scholar 

  115. Sanz, J. M. et al. Possible protective role of the 489C>T P2X7R polymorphism in Alzheimer's disease. Exp. Gerontol. 60, 117–119 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Sanz, J. M. et al. Activation of microglia by amyloidβ requires P2X7 receptor expression. J. Immunol. 182, 4378–4385 (2009).

    Article  CAS  PubMed  Google Scholar 

  117. Ni, J., Wang, P., Zhang, J., Chen, W. & Gu, L. Silencing of the P2X7 receptor enhances amyloid-β phagocytosis by microglia. Biochem. Biophys. Res. Commun. 434, 363–369 (2013).

    Article  CAS  PubMed  Google Scholar 

  118. Diaz-Hernandez, J. I. et al. In vivo P2X7 inhibition reduces amyloid plaques in Alzheimer's disease through GSK3β and secretases. Neurobiol. Aging 33, 1816–1828 (2012).

    Article  CAS  PubMed  Google Scholar 

  119. Clark, A. K., Gentry, C., Bradbury, E. J., McMahon, S. B. & Malcangio, M. Role of spinal microglia in rat models of peripheral nerve injury and inflammation. Eur. J. Pain Lond. Engl. 11, 223–230 (2007).

    Article  Google Scholar 

  120. Tsuda, M. et al. P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 424, 778–783 (2003). A landmark study providing evidence for P2X4 in spinal cord microglia as a drug target in neuropathic pain.

    Article  CAS  PubMed  Google Scholar 

  121. Schäfers, M., Svensson, C. I., Sommer, C. & Sorkin, L. S. Tumor necrosis factor-alpha induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons. J. Neurosci. 23, 2517–2521 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  122. Chu, Y.-X., Zhang, Y., Zhang, Y.-Q. & Zhao, Z.-Q. Involvement of microglial P2X7 receptors and downstream signaling pathways in long-term potentiation of spinal nociceptive responses. Brain. Behav. Immun. 24, 1176–1189 (2010).

    Article  CAS  PubMed  Google Scholar 

  123. Clark, A. K. et al. P2X7-dependent release of interleukin-1β and nociception in the spinal cord following lipopolysaccharide. J. Neurosci. 30, 573–582 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Zhou, D., Chen, M.-L., Zhang, Y.-Q. & Zhao, Z.-Q. Involvement of spinal microglial P2X7 receptor in generation of tolerance to morphine analgesia in rats. J. Neurosci. 30, 8042–8047 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. He, W.-J. et al. Spinal P2X7 receptor mediates microglia activation-induced neuropathic pain in the sciatic nerve injury rat model. Behav. Brain Res. 226, 163–170 (2012).

    Article  CAS  PubMed  Google Scholar 

  126. Clark, A. K., Grist, J., Al-Kashi, A., Perretti, M. & Malcangio, M. Spinal cathepsin S and fractalkine contribute to chronic pain in the collagen-induced arthritis model. Arthritis Rheum. 64, 2038–2047 (2012).

    Article  CAS  PubMed  Google Scholar 

  127. Clark, A. K., Wodarski, R., Guida, F., Sasso, O. & Malcangio, M. Cathepsin S release from primary cultured microglia is regulated by the P2X7 receptor. Glia 58, 1710–1726 (2010).

    Article  PubMed  Google Scholar 

  128. Clark, A. K., Yip, P. K. & Malcangio, M. The liberation of fractalkine in the dorsal horn requires microglial cathepsin S. J. Neurosci. 29, 6945–6954 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Jung, H. et al. Visualization of chemokine receptor activation in transgenic mice reveals peripheral activation of CCR2 receptors in states of neuropathic pain. J. Neurosci. 29, 8051–8062 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Zhang, J. et al. Expression of CCR2 in both resident and bone marrow-derived microglia plays a critical role in neuropathic pain. J. Neurosci. 27, 12396–12406 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Gao, Y.-J. et al. JNK-induced MCP-1 production in spinal cord astrocytes contributes to central sensitization and neuropathic pain. J. Neurosci. 29, 4096–4108 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Biber, K. & Boddeke, E. Neuronal CC chemokines: the distinct roles of CCL21 and CCL2 in neuropathic pain. Front. Cell. Neurosci. 8, 210 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Ibrahim, M. M. et al. Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: pain inhibition by receptors not present in the CNS. Proc. Natl Acad. Sci. USA 100, 10529–10533 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Malan, T. P. et al. CB2 cannabinoid receptor-mediated peripheral antinociception. Pain 93, 239–245 (2001).

    Article  CAS  PubMed  Google Scholar 

  135. Zhang, J. et al. Induction of CB2 receptor expression in the rat spinal cord of neuropathic but not inflammatory chronic pain models. Eur. J. Neurosci. 17, 2750–2754 (2003).

    Article  PubMed  Google Scholar 

  136. Romero-Sandoval, E. A., Horvath, R., Landry, R. P. & DeLeo, J. A. Cannabinoid receptor type 2 activation induces a microglial anti-inflammatory phenotype and reduces migration via MKP induction and ERK dephosphorylation. Mol. Pain 5, 25 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Chahrour, M. & Zoghbi, H. Y. The story of Rett syndrome: from clinic to neurobiology. Neuron 56, 422–437 (2007).

    Article  CAS  PubMed  Google Scholar 

  138. Maezawa, I. & Jin, L.-W. Rett syndrome microglia damage dendrites and synapses by the elevated release of glutamate. J. Neurosci. 30, 5346–5356 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Maezawa, I., Swanberg, S., Harvey, D., LaSalle, J. M. & Jin, L.-W. Rett syndrome astrocytes are abnormal and spread MeCP2 deficiency through gap junctions. J. Neurosci. 29, 5051–5061 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Derecki, N. C. et al. Wild-type microglia arrest pathology in a mouse model of Rett syndrome. Nature 484, 105–109 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Wang, J. et al. Wild-type microglia do not reverse pathology in mouse models of Rett syndrome. Nature 521, E1–E4 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Barden, N. et al. Analysis of single nucleotide polymorphisms in genes in the chromosome 12Q24.31 region points to P2RX7 as a susceptibility gene to bipolar affective disorder. Am. J. Med. Genet. 141B, 374–382 (2006).

    Article  CAS  PubMed  Google Scholar 

  143. Lucae, S. et al. P2RX7, a gene coding for a purinergic ligand-gated ion channel, is associated with major depressive disorder. Hum. Mol. Genet. 15, 2438–2445 (2006).

    Article  CAS  PubMed  Google Scholar 

  144. Boucher, A. A. et al. Resilience and reduced c-Fos expression in P2X7 receptor knockout mice exposed to repeated forced swim test. Neuroscience 189, 170–177 (2011).

    Article  CAS  PubMed  Google Scholar 

  145. Basso, A. M. et al. Behavioral profile of P2X7 receptor knockout mice in animal models of depression and anxiety: relevance for neuropsychiatric disorders. Behav. Brain Res. 198, 83–90 (2009).

    Article  CAS  PubMed  Google Scholar 

  146. Wilkinson, S. M. et al. The first CNS-active carborane: a novel P2X7 receptor antagonist with antidepressant activity. ACS Chem. Neurosci. 5, 335–339 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Gibney, S. M. & Drexhage, H. A. Evidence for a dysregulated immune system in the etiology of psychiatric disorders. J. Neuroimmune Pharmacol. 8, 900–920 (2013).

    Article  PubMed  Google Scholar 

  148. Haarman, B. C. M. B. et al. Neuroinflammation in bipolar disorder — a [11C]-(R)-PK11195 positron emission tomography study. Brain. Behav. Immun. 40, 219–225 (2014).

    Article  CAS  PubMed  Google Scholar 

  149. Bonaccorso, S. et al. Increased depressive ratings in patients with hepatitis C receiving interferon-α-based immunotherapy are related to interferon-α-induced changes in the serotonergic system. J. Clin. Psychopharmacol. 22, 86–90 (2002).

    Article  CAS  PubMed  Google Scholar 

  150. Capuron, L. et al. Interferon-alpha-induced changes in tryptophan metabolism. relationship to depression and paroxetine treatment. Biol. Psychiatry 54, 906–914 (2003).

    Article  CAS  PubMed  Google Scholar 

  151. Comai, S. et al. Effects of PEG-interferon alpha plus ribavirin on tryptophan metabolism in patients with chronic hepatitis C. Pharmacol. Res. 63, 85–92 (2011).

    Article  CAS  PubMed  Google Scholar 

  152. Carvalho, L. A. et al. Inflammatory activation is associated with a reduced glucocorticoid receptor alpha/beta expression ratio in monocytes of in patients with melancholic major depressive disorder. Transl. Psychiatry 4, e344 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Drexhage, R. C. et al. The activation of monocyte and T cell networks in patients with bipolar disorder. Brain. Behav. Immun. 25, 1206–1213 (2011).

    Article  CAS  PubMed  Google Scholar 

  154. Campbell, B. M., Charych, E., Lee, A. W. & Möller, T. Kynurenines in CNS disease: regulation by inflammatory cytokines. Front. Neurosci. 8, 12 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  155. McGeer, P. L. & McGeer, E. G. Inflammatory processes in amyotrophic lateral sclerosis. Muscle Nerve 26, 459–470 (2002).

    Article  CAS  PubMed  Google Scholar 

  156. Beers, D. R. et al. Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis. Proc. Natl Acad. Sci. USA 103, 16021–16026 (2006). This study identifies PU.1 as a crucial transcription factor and provides the first data that bone marrow transfer is beneficial in an animal model of ALS.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Koval, E. D. et al. Method for widespread microRNA-155 inhibition prolongs survival in ALS-model mice. Hum. Mol. Genet. 22, 4127–4135 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Butovsky, O. et al. Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS. J. Clin. Invest. 122, 3063–3087 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Nakada, M., Okada, Y. & Yamashita, J. The role of matrix metalloproteinases in glioma invasion. Front. Biosci. J. Virtual Libr. 8, e261–e269 (2003).

    Article  CAS  Google Scholar 

  160. Markovic, D. S. et al. Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion. Proc. Natl Acad. Sci. USA 106, 12530–12535 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Könnecke, H. & Bechmann, I. The role of microglia and matrix metalloproteinases involvement in neuroinflammation and gliomas. Clin. Dev. Immunol. 2013, 914104 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Da Fonseca, A. C. C. & Badie, B. Microglia and macrophages in malignant gliomas: recent discoveries and implications for promising therapies. Clin. Dev. Immunol. 2013, 264124 (2013).

    PubMed  Google Scholar 

  163. Coniglio, S. J. et al. Microglial stimulation of glioblastoma invasion involves epidermal growth factor receptor (EGFR) and colony stimulating factor 1 receptor (CSF-1R) signaling. Mol. Med. 18, 519–527 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Kalliomäki, J. et al. A randomized, double-blind, placebo-controlled trial of a chemokine receptor 2 (CCR2) antagonist in posttraumatic neuralgia. Pain 154, 761–767 (2013).

    Article  CAS  PubMed  Google Scholar 

  165. Sorge, R. E. et al. Genetically determined P2X7 receptor pore formation regulates variability in chronic pain sensitivity. Nat. Med. 18, 595–599 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Keystone, E. C. et al. Clinical evaluation of the efficacy of the P2X7 purinergic receptor antagonist AZD9056 on the signs and symptoms of rheumatoid arthritis in patients with active disease despite treatment with methotrexate or sulphasalazine. Ann. Rheum. Dis. 71, 1630–1635 (2012).

    Article  CAS  PubMed  Google Scholar 

  167. Stock, T. C. et al. Efficacy and safety of CE-224,535, an antagonist of P2X7 receptor, in treatment of patients with rheumatoid arthritis inadequately controlled by methotrexate. J. Rheumatol. 39, 720–727 (2012).

    Article  CAS  PubMed  Google Scholar 

  168. Ali, Z. et al. Pharmacokinetic and pharmacodynamic profiling of a P2X7 receptor allosteric modulator GSK1482160 in healthy human subjects. Br. J. Clin. Pharmacol. 75, 197–207 (2013).

    Article  CAS  PubMed  Google Scholar 

  169. Lord, B. et al. Pharmacology of a novel central nervous system-penetrant P2X7 antagonist JNJ-42253432. J. Pharmacol. Exp. Ther. 351, 628–641 (2014).

    Article  CAS  PubMed  Google Scholar 

  170. Bhattacharya, A. et al. Pharmacological characterization of a novel centrally permeable P2X7 receptor antagonist: JNJ-47965567. Br. J. Pharmacol. 170, 624–640 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Garber, K. Genentech's Alzheimer's antibody trial to study disease prevention. Nat. Biotech. 30, 731–732 (2012).

    Article  CAS  Google Scholar 

  173. Spencer, B. & Masliah, E. Immunotherapy for Alzheimer's disease: past, present and future. Front. Aging Neurosci. 6, 114 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Bohrmann, B. et al. Gantenerumab: a novel human anti-Aβ antibody demonstrates sustained cerebral amyloid-β binding and elicits cell-mediated removal of human amyloid-β. J. Alzheimers Dis. 28, 49–69 (2012).

    Article  CAS  PubMed  Google Scholar 

  175. Ostrowitzki, S. et al. Mechanism of amyloid removal in patients with Alzheimer disease treated with gantenerumab. Arch. Neurol. 69, 198–207 (2012).

    Article  PubMed  Google Scholar 

  176. Wisniewski, T. & Goñi, F. Immunotherapeutic approaches for Alzheimer's disease. Neuron 85, 1162–1176 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Yang, C. & Xiao, S. New developments of clinical trial in immunotherapy for Alzheimer's disease. Curr. Pharm. Biotechnol. 16, 484–491 (2015).

    Article  CAS  PubMed  Google Scholar 

  178. Raghavendra, V., Tanga, F. & DeLeo, J. A. Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy. J. Pharmacol. Exp. Ther. 306, 624–630 (2003).

    Article  CAS  PubMed  Google Scholar 

  179. Ledeboer, A. et al. Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation. Pain 115, 71–83 (2005).

    Article  CAS  PubMed  Google Scholar 

  180. Mika, J., Osikowicz, M., Makuch, W. & Przewlocka, B. Minocycline and pentoxifylline attenuate allodynia and hyperalgesia and potentiate the effects of morphine in rat and mouse models of neuropathic pain. Eur. J. Pharmacol. 560, 142–149 (2007).

    Article  CAS  PubMed  Google Scholar 

  181. Osikowicz, M. et al. Glial inhibitors influence the mRNA and protein levels of mGlu2/3, 5 and 7 receptors and potentiate the analgesic effects of their ligands in a mouse model of neuropathic pain. Pain 147, 175–186 (2009).

    Article  CAS  PubMed  Google Scholar 

  182. Redin, G. S. Antibacterial activity in mice of minocycline, a new tetracycline. Antimicrob. Agents Chemother. 6, 371–376 (1966).

    CAS  PubMed  Google Scholar 

  183. Amin, A. R. et al. A novel mechanism of action of tetracyclines: effects on nitric oxide synthases. Proc. Natl Acad. Sci. USA 93, 14014–14019 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Chen, M. et al. Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat. Med. 6, 797–801 (2000).

    Article  CAS  PubMed  Google Scholar 

  185. Sadowski, T. & Steinmeyer, J. Minocycline inhibits the production of inducible nitric oxide synthase in articular chondrocytes. J. Rheumatol. 28, 336–340 (2001).

    CAS  PubMed  Google Scholar 

  186. Dunston, C. R., Griffiths, H. R., Lambert, P. A., Staddon, S. & Vernallis, A. B. Proteomic analysis of the anti-inflammatory action of minocycline. Proteomics 11, 42–51 (2011).

    Article  CAS  PubMed  Google Scholar 

  187. Szeto, G. L., Pomerantz, J. L., Graham, D. R. M. & Clements, J. E. Minocycline suppresses activation of nuclear factor of activated T cells 1 (NFAT1) in human CD4+ T cells. J. Biol. Chem. 286, 11275–11282 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Huang, W. C. et al. Direct protection of cultured neurons from ischemia-like injury by minocycline. Anat. Cell Biol. 43, 325–331 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  189. Schildknecht, S. et al. Neuroprotection by minocycline caused by direct and specific scavenging of peroxynitrite. J. Biol. Chem. 286, 4991–5002 (2011).

    Article  CAS  PubMed  Google Scholar 

  190. Hashimoto, K. & Ishima, T. A novel target of action of minocycline in NGF-induced neurite outgrowth in PC12 cells: translation initiation [corrected] factor eIF4AI. PLoS ONE 5, e15430 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Ossola, B. et al. Minocycline protects SH-SY5Y cells from 6-hydroxydopamine by inhibiting both caspase-dependent and -independent programmed cell death. J. Neurosci. Res. 90, 682–690 (2012).

    Article  CAS  PubMed  Google Scholar 

  192. Hughes, E. H. et al. Minocycline delays photoreceptor death in the rds mouse through a microglia-independent mechanism. Exp. Eye Res. 78, 1077–1084 (2004).

    Article  CAS  PubMed  Google Scholar 

  193. Fendrick, S. E., Miller, K. R. & Streit, W. J. Minocycline does not inhibit microglia proliferation or neuronal regeneration in the facial nucleus following crush injury. Neurosci. Lett. 385, 220–223 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  195. Ji, R.-R. Targeting microglial purinergic signaling to improve morphine analgesia. Pain 150, 377–378 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  196. Koizumi, S., Ohsawa, K., Inoue, K. & Kohsaka, S. Purinergic receptors in microglia: functional modal shifts of microglia mediated by P2 and P1 receptors. Glia 61, 47–54 (2013).

    Article  PubMed  Google Scholar 

  197. Crain, J. M., Nikodemova, M. & Watters, J. J. Expression of P2 nucleotide receptors varies with age and sex in murine brain microglia. J. Neuroinflamm. 6, 24 (2009).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  199. Clark, A. K. & Malcangio, M. Fractalkine/CX3CR1 signaling during neuropathic pain. Front. Cell. Neurosci. 8, 121 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Bhaskar, K. et al. Microglial derived tumor necrosis factor-α drives Alzheimer's disease-related neuronal cell cycle events. Neurobiol. Dis. 62, 273–285 (2014).

    Article  CAS  PubMed  Google Scholar 

  201. Lee, S. et al. Opposing effects of membrane-anchored CX3CL1 on amyloid and tau pathologies via the p38 MAPK pathway. J. Neurosci. 34, 12538–12546 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Limatola, C. & Ransohoff, R. M. Modulating neurotoxicity through CX3CL1/CX3CR1 signaling. Front. Cell. Neurosci. 8, 229 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Leist, M. & Hartung, T. Inflammatory findings on species extrapolations: humans are definitely no 70-kg mice. Arch. Toxicol. 87, 563–567 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Mestas, J. & Hughes, C. C. W. Of mice and not men: differences between mouse and human immunology. J. Immunol. 172, 2731–2738 (2004).

    Article  CAS  PubMed  Google Scholar 

  205. Payne, K. J. & Crooks, G. M. Immune-cell lineage commitment: translation from mice to humans. Immunity 26, 674–677 (2007).

    Article  CAS  PubMed  Google Scholar 

  206. Seok, J. et al. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc. Natl Acad. Sci. USA 110, 3507–3512 (2013). This paper provides convincing evidence that inflammation is different in mice and humans.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Shay, T. et al. Conservation and divergence in the transcriptional programs of the human and mouse immune systems. Proc. Natl Acad. Sci. USA 110, 2946–2951 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Smith, A. M. & Dragunow, M. The human side of microglia. Trends Neurosci. 37, 125–135 (2014).

    Article  CAS  PubMed  Google Scholar 

  209. Streit, W. J., Xue, Q.-S., Tischer, J. & Bechmann, I. Microglial pathology. Acta Neuropathol. Commun. 2, 142 (2014). This study brings forward the idea that human microglia become senescent or dysfunctional with ageing, thus rendering the brain vulnerable to the development of age-related neurodegenerative diseases.

    Article  PubMed  PubMed Central  Google Scholar 

  210. Becher, B. & Antel, J. P. Comparison of phenotypic and functional properties of immediately ex vivo and cultured human adult microglia. Glia 18, 1–10 (1996).

    Article  CAS  PubMed  Google Scholar 

  211. Becher, B., Fedorowicz, V. & Antel, J. P. Regulation of CD14 expression on human adult central nervous system-derived microglia. J. Neurosci. Res. 45, 375–381 (1996).

    Article  CAS  PubMed  Google Scholar 

  212. Dick, A. D., Pell, M., Brew, B. J., Foulcher, E. & Sedgwick, J. D. Direct ex vivo flow cytometric analysis of human microglial cell CD4 expression: examination of central nervous system biopsy specimens from HIV-seropositive patients and patients with other neurological disease. AIDS 11, 1699–1708 (1997).

    Article  CAS  PubMed  Google Scholar 

  213. Jack, C. S. et al. TLR signaling tailors innate immune responses in human microglia and astrocytes. J. Immunol. 175, 4320–4330 (2005).

    Article  CAS  PubMed  Google Scholar 

  214. Walter, S. et al. The LPS receptor, CD14, in experimental autoimmune encephalomyelitis and multiple sclerosis. Cell. Physiol. Biochem. 17, 167–172 (2006).

    Article  CAS  PubMed  Google Scholar 

  215. Jiang, Z. et al. CD14 is required for MyD88-independent LPS signaling. Nat. Immunol. 6, 565–570 (2005).

    Article  CAS  PubMed  Google Scholar 

  216. Melief, J. et al. Phenotyping primary human microglia: tight regulation of LPS responsiveness. Glia 60, 1506–1517 (2012). This report provides the first data questioning the general responsiveness of human microglia to lipopolysaccharide.

    Article  PubMed  Google Scholar 

  217. Schneemann, M. & Schoeden, G. Macrophage biology and immunology: man is not a mouse. J. Leukoc. Biol. 81, 579; discussion 580 (2007).

    Article  CAS  PubMed  Google Scholar 

  218. Landry, R. P., Jacobs, V. L., Romero-Sandoval, E. A. & DeLeo, J. A. Propentofylline, a CNS glial modulator does not decrease pain in post-herpetic neuralgia patients: in vitro evidence for differential responses in human and rodent microglia and macrophages. Exp. Neurol. 234, 340–350 (2012).

    Article  CAS  PubMed  Google Scholar 

  219. Watkins, L. R. et al. Commentary on Landry et al. “Propentofylline, a CNS glial modulator, does not decrease pain in post-herpetic neuralgia patients: in vitro evidence for differential responses in human and rodent microglia and macrophages”. Exp. Neurol. 234, 351–353 (2012).

    Article  CAS  PubMed  Google Scholar 

  220. Perrin, S. Preclinical research: make mouse studies work. Nature 507, 423–425 (2014).

    Article  PubMed  Google Scholar 

  221. Bishop, N. A., Lu, T. & Yankner, B. A. Neural mechanisms of ageing and cognitive decline. Nature 464, 529–535 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Norden, D. M. & Godbout, J. P. Review: microglia of the aged brain: primed to be activated and resistant to regulation. Neuropathol. Appl. Neurobiol. 39, 19–34 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Sierra, A., Gottfried-Blackmore, A. C., McEwen, B. S. & Bulloch, K. Microglia derived from aging mice exhibit an altered inflammatory profile. Glia 55, 412–424 (2007).

    Article  PubMed  Google Scholar 

  224. Perry, V. H. & Holmes, C. Microglial priming in neurodegenerative disease. Nat. Rev. Neurol. 10, 217–224 (2014).

    Article  CAS  PubMed  Google Scholar 

  225. Lull, M. E. & Block, M. L. Microglial activation and chronic neurodegeneration. Neurotherapeutics 7, 354–365 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Henry, C. J., Huang, Y., Wynne, A. M. & Godbout, J. P. Peripheral lipopolysaccharide (LPS) challenge promotes microglial hyperactivity in aged mice that is associated with exaggerated induction of both pro-inflammatory IL-1β and anti-inflammatory IL-10 cytokines. Brain. Behav. Immun. 23, 309–317 (2009).

    Article  CAS  PubMed  Google Scholar 

  227. Fenn, A. M., Henry, C. J., Huang, Y., Dugan, A. & Godbout, J. P. Lipopolysaccharide-induced interleukin (IL)-4 receptor-α expression and corresponding sensitivity to the M2 promoting effects of IL-4 are impaired in microglia of aged mice. Brain. Behav. Immun. 26, 766–777 (2012).

    Article  CAS  PubMed  Google Scholar 

  228. Perry, V. H., Cunningham, C. & Holmes, C. Systemic infections and inflammation affect chronic neurodegeneration. Nat. Rev. Immunol. 7, 161–167 (2007).

    Article  CAS  PubMed  Google Scholar 

  229. Streit, W. J. & Xue, Q.-S. Human CNS immune senescence and neurodegeneration. Curr. Opin. Immunol. 29, 93–96 (2014).

    Article  CAS  PubMed  Google Scholar 

  230. Streit, W. J. Microglial senescence: does the brain's immune system have an expiration date? Trends Neurosci. 29, 506–510 (2006).

    Article  CAS  PubMed  Google Scholar 

  231. Calado, R. T. & Dumitriu, B. Telomere dynamics in mice and humans. Semin. Hematol. 50, 165–174 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Hayflick, L. The limited in vitro life time of human diploid cell strains. Exp. Cell Res. 37, 614–636 (1965).

    Article  CAS  PubMed  Google Scholar 

  233. Allsopp, R. C. et al. Telomere shortening is associated with cell division in vitro and in vivo. Exp. Cell Res. 220, 194–200 (1995).

    Article  CAS  PubMed  Google Scholar 

  234. Campisi, J. & d' Adda di Fagagna, F. Cellular senescence: when bad things happen to good cells. Nat. Rev. Mol. Cell. Biol. 8, 729–740 (2007).

    Article  CAS  PubMed  Google Scholar 

  235. Lansdorp, P. M. Telomeres and disease. EMBO J. 28, 2532–2540 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Flanary, B. E. & Streit, W. J. Progressive telomere shortening occurs in cultured rat microglia, but not astrocytes. Glia 45, 75–88 (2004).

    Article  PubMed  Google Scholar 

  237. Olah, M. et al. An optimized protocol for the acute isolation of human microglia from autopsy brain samples. Glia 60, 96–111 (2012).

    Article  PubMed  Google Scholar 

  238. Chiu, I. M. et al. A neurodegeneration-specific gene-expression signature of acutely isolated microglia from an amyotrophic lateral sclerosis mouse model. Cell Rep. 4, 385–401 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Orre, M. et al. Isolation of glia from Alzheimer's mice reveals inflammation and dysfunction. Neurobiol. Aging 35, 2746–2760 (2014).

    Article  CAS  PubMed  Google Scholar 

  240. Bartlett, R., Stokes, L. & Sluyter, R. The P2X7 receptor channel: recent developments and the use of P2X7 antagonists in models of disease. Pharmacol. Rev. 66, 638–675 (2014).

    Article  CAS  PubMed  Google Scholar 

  241. Donnelly-Roberts, D. L., Namovic, M. T., Han, P. & Jarvis, M. F. Mammalian P2X7 receptor pharmacology: comparison of recombinant mouse, rat and human P2X7 receptors. Br. J. Pharmacol. 157, 1203–1214 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Sluyter, R. & Stokes, L. Significance of P2X7 receptor variants to human health and disease. Recent Pat. DNA Gene Seq. 5, 41–54 (2011).

    Article  CAS  PubMed  Google Scholar 

  243. Yiangou, Y. et al. COX-2, CB2 and P2X7-immunoreactivities are increased in activated microglial cells/macrophages of multiple sclerosis and amyotrophic lateral sclerosis spinal cord. BMC Neurol. 6, 12 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Grygorowicz, T., Sulejczak, D. & Struzynska, L. Expression of purinergic P2X7 receptor in rat brain during the symptomatic phase of experimental autoimmune encephalomyelitis and after recovery of neurological deficits. Acta Neurobiol. Exp. (Wars) 71, 65–73 (2011).

    Google Scholar 

  245. Witting, A. et al. Experimental autoimmune encephalomyelitis disrupts endocannabinoid-mediated neuroprotection. Proc. Natl Acad. Sci. USA 103, 6362–6367 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. Caragnano, M. et al. Monocytes P2X7 purinergic receptor is modulated by glatiramer acetate in multiple sclerosis. J. Neuroimmunol. 245, 93–97 (2012).

    Article  CAS  PubMed  Google Scholar 

  247. Sigurdsson, E. M., Scholtzova, H., Mehta, P. D., Frangione, B. & Wisniewski, T. Immunization with a nontoxic/nonfibrillar amyloid-β homologous peptide reduces Alzheimer's disease-associated pathology in transgenic mice. Am. J. Pathol. 159, 439–447 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. Kellner, A. et al. Autoantibodies against β-amyloid are common in Alzheimer's disease and help control plaque burden. Ann. Neurol. 65, 24–31 (2009).

    Article  PubMed  Google Scholar 

  249. Zotova, E. et al. Inflammatory components in human Alzheimer's disease and after active amyloid-β42 immunization. Brain J. Neurol. 136, 2677–2696 (2013).

    Article  Google Scholar 

  250. Zotova, E. et al. Microglial alterations in human Alzheimer's disease following Aβ42 immunization. Neuropathol. Appl. Neurobiol. 37, 513–524 (2011).

    Article  CAS  PubMed  Google Scholar 

  251. Walker, D. G. et al. Association of CD33 polymorphism rs3865444 with Alzheimer's disease pathology and CD33 expression in human cerebral cortex. Neurobiol. Aging 36, 517–582 (2015).

    Article  CAS  Google Scholar 

  252. Frank, S. et al. TREM2 is upregulated in amyloid plaque-associated microglia in aged APP23 transgenic mice. Glia 56, 1438–1447 (2008).

    Article  PubMed  Google Scholar 

  253. Schmid, C. D. et al. Heterogeneous expression of the triggering receptor expressed on myeloid cells-2 on adult murine microglia. J. Neurochem. 83, 1309–1320 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. Lucin, K. M. et al. Microglial beclin 1 regulates retromer trafficking and phagocytosis and is impaired in Alzheimer's disease. Neuron 79, 873–886 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. Lue, L.-F. et al. TREM2 protein expression changes correlate with Alzheimer's disease neurodegenerative pathologies in post-mortem temporal cortices. Brain Pathol. 25, 469–480 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  256. 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 

  257. Naert, G. & Rivest, S. CC chemokine receptor 2 deficiency aggravates cognitive impairments and amyloid pathology in a transgenic mouse model of Alzheimer's disease. J. Neurosci. 31, 6208–6220 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  258. Liu, Y. et al. IKKβ deficiency in myeloid cells ameliorates Alzheimer's disease-related symptoms and pathology. J. Neurosci. 34, 12982–12999 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  259. Naert, G. & Rivest, S. Age-related changes in synaptic markers and monocyte subsets link the cognitive decline of APPSwe/PS1 mice. Front. Cell. Neurosci. 6, 51 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  260. Biber, K. et al. Neuronal CCL21 up-regulates microglia P2X4 expression and initiates neuropathic pain development. EMBO J. 30, 1864–1873 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  261. Staniland, A. A. et al. Reduced inflammatory and neuropathic pain and decreased spinal microglial response in fractalkine receptor (CX3CR1) knockout mice. J. Neurochem. 114, 1143–1157 (2010).

    CAS  PubMed  Google Scholar 

  262. Abbadie, C. et al. Impaired neuropathic pain responses in mice lacking the chemokine receptor CCR2. Proc. Natl Acad. Sci. USA 100, 7947–7952 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. Padi, S. S. V. et al. Attenuation of rodent neuropathic pain by an orally active peptide, RAP-103, which potently blocks CCR2- and CCR5-mediated monocyte chemotaxis and inflammation. Pain 153, 95–106 (2012).

    Article  CAS  PubMed  Google Scholar 

  264. Old, E. A. et al. Monocytes expressing CX3CR1 orchestrate the development of vincristine-induced pain. J. Clin. Invest. 124, 2023–2036 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  265. Corona, A. W. et al. Indoleamine 2,3-dioxygenase inhibition attenuates lipopolysaccharide induced persistent microglial activation and depressive-like complications in fractalkine receptor (CX3CR1)-deficient mice. Brain. Behav. Immun. 31, 134–142 (2013).

    Article  CAS  PubMed  Google Scholar 

  266. O'Connor, J. C. et al. Interferon-γ and tumor necrosis factor-α mediate the upregulation of indoleamine 2,3-dioxygenase and the induction of depressive-like behavior in mice in response to bacillus Calmette-Guérin. J. Neurosci. 29, 4200–4209 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  267. Busse, M. et al. Decreased quinolinic acid in the hippocampus of depressive patients: evidence for local anti-inflammatory and neuroprotective responses? Eur. Arch. Psychiatry Clin. Neurosci. 265, 321–329 (2015).

    Article  PubMed  Google Scholar 

  268. Gos, T. et al. Reduced microglial immunoreactivity for endogenous NMDA receptor agonist quinolinic acid in the hippocampus of schizophrenia patients. Brain. Behav. Immun. 41, 59–64 (2014).

    Article  CAS  PubMed  Google Scholar 

  269. Wang, H. et al. S100B promotes glioma growth through chemoattraction of myeloid-derived macrophages. Clin. Cancer Res. 19, 3764–3775 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  270. Xu, S. et al. Effect of miR-142-3p on the M2 macrophage and therapeutic efficacy against murine glioblastoma. J. Natl. Cancer Inst. 106 (2014).

  271. Panza, F. et al. Efficacy and safety studies of gantenerumab in patients with Alzheimer's disease. Expert Rev. Neurother. 14, 973–986 (2014).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors apologize to all those colleagues whose work was discussed without proper citation owing to space constraints. M.P. receives support from the Federal Ministry of Education and Research (BMBF)-funded competence network of multiple sclerosis (KKNMS), the Hertie Foundation (GHST), the Sobek Foundation, the Fritz Thyssen Foundation and the German Research Foundation (DFG; grants SFB 992 and FOR 1336). K.B. receives support from the BMBF-funded competence network of neurodegenerative disease (KNDD), the BMBF project ReelinSys and the DFG (grants BI 668/5-1 and BI 668/2-2 (FOR 1336)).

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Authors and Affiliations

  1. Department of Psychiatry and Psychotherapy, Section of Molecular Psychiatry, University of Freiburg, Freiburg, 79104, Germany

    Knut Biber

  2. Neuroinflammation Disease Biology Unit, Lundbeck Research USA, Paramus, 07652, New Jersey, USA

    Thomas Möller

  3. Department of Neurology, School of Medicine, University of Washington, Seattle, 98195, Washington, USA

    Thomas Möller

  4. Department of Neuroscience, Section of Medical Physiology, University of Groningen, University Medical Center Groningen, Groningen, 9713, The Netherlands

    Knut Biber & Erik Boddeke

  5. Institute of Neuropathology, University of Freiburg, Freiburg, 79106, Germany

    Marco Prinz

  6. BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, 79104, Germany

    Marco Prinz

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  1. Knut Biber
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  2. Thomas Möller
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  3. Erik Boddeke
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Correspondence to Knut Biber or Marco Prinz.

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Biber, K., Möller, T., Boddeke, E. et al. Central nervous system myeloid cells as drug targets: current status and translational challenges. Nat Rev Drug Discov 15, 110–124 (2016). https://doi.org/10.1038/nrd.2015.14

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