211
Views
0
CrossRef citations to date
0
Altmetric
Review

Identification of glia phenotype modulators based on select glial function regulatory signaling pathways

&
Pages 627-641 | Received 04 Feb 2018, Accepted 13 Apr 2018, Published online: 20 Apr 2018

References

  • Pankevich DE, Altevogt BM, Dunlop J, et al. Improving and accelerating drug development for nervous system disorders. Neuron. 2014;84(3):546–553.
  • Tufts Center for the Study of Drug Development. Drugs to treat CNS diseases take 35% longer to develop than other drugs. 2012; [cited 2013 August 28]. Available from: http://csdd.tufts.edu/news/complete_story/pr_ir_marapr_2012.
  • Glass CK, Saijo K, Winner B, et al. Mechanisms underlying inflammation in neurodegeneration. Cell. 2010;140(6):918–934.
  • Block ML, Zecca L, Hong JS. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci. 2007;8(1):57–69.
  • Hellwig S, Heinrich A, Biber K. The brain’s best friend: microglial neurotoxicity revisited. Front Cell Neurosci. 2013;7:71.
  • Colonna M, Butovsky O. Microglia function in the central nervous system during health and neurodegeneration. Annu Rev Immunol. 2017;35:441–468.
  • Suk K. Glial phenotype modulators. Oncotarget. 2017;8(14):22309–22310.
  • Jha MK, Lee WH, Suk K. Functional polarization of neuroglia: implications in neuroinflammation and neurological disorders. Biochem Pharmacol. 2016;103:1–16.
  • Olah M, Amor S, Brouwer N, et al. Identification of a microglia phenotype supportive of remyelination. Glia. 2012;60(2):306–321.
  • Figuera-Losada M, Rojas C, Slusher BS. Inhibition of microglia activation as a phenotypic assay in early drug discovery. J Biomol Screen. 2014;19(1):17–31.
  • Smith AM, Dragunow M. The human side of microglia. Trends Neurosci. 2014;37(3):125–135.
  • Sousa C, Biber K, Michelucci A. Cellular and molecular characterization of microglia: a unique immune cell population. Front Immunol. 2017;8:198.
  • Smith AM, Gibbons HM, Oldfield RL, et al. M-CSF increases proliferation and phagocytosis while modulating receptor and transcription factor expression in adult human microglia. J Neuroinflammation. 2013;10:85.
  • Melief J, Koning N, Schuurman KG, et al. Phenotyping primary human microglia: tight regulation of LPS responsiveness. Glia. 2012;60(10):1506–1517.
  • Melief J, Sneeboer MA, Litjens M, et al. Characterizing primary human microglia: a comparative study with myeloid subsets and culture models. Glia. 2016;64(11):1857–1868.
  • Landry RP, Jacobs VL, Romero-Sandoval EA, 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. 2012;234(2):340–350.
  • Janabi N. Selective inhibition of cyclooxygenase-2 expression by 15-deoxy-Delta(12,14)(12,14)-prostaglandin J(2) in activated human astrocytes, but not in human brain macrophages. J Immunol. 2002;168(9):4747–4755.
  • Ding M, Pierre BAS, Parkinson JF, et al. Inducible nitric-oxide synthase and nitric oxide production in human fetal astrocytes and microglia. A kinetic analysis. J Biol Chem. 1997;272(17):11327–11335.
  • Bennett ML, Bennett FC, Liddelow SA, et al. New tools for studying microglia in the mouse and human CNS. Proc Natl Acad Sci U S A. 2016;113(12):E1738–46.
  • Butovsky O, Jedrychowski MP, Moore CS, et al. Identification of a unique TGF-beta-dependent molecular and functional signature in microglia. Nat Neurosci. 2014;17(1):131–143.
  • Hashioka S, Klegeris A, Schwab C, et al. Differential expression of interferon-gamma receptor on human glial cells in vivo and in vitro. J Neuroimmunol. 2010;225(1–2):91–99.
  • Mildner A, Huang H, Radke J, et al. P2Y12 receptor is expressed on human microglia under physiological conditions throughout development and is sensitive to neuroinflammatory diseases. Glia. 2017;65(2):375–387.
  • Satoh J, Kino Y, Asahina N, et al. TMEM119 marks a subset of microglia in the human brain. Neuropathology. 2016;36(1):39–49.
  • Grabert K, Michoel T, Karavolos MH, et al. Microglial brain region-dependent diversity and selective regional sensitivities to aging. Nat Neurosci. 2016;19(3):504–516.
  • Doorn KJ, Breve JJ, Drukarch B, et al. Brain region-specific gene expression profiles in freshly isolated rat microglia. Front Cell Neurosci. 2015;9:84.
  • Muffat J, Li Y, Yuan B, et al. Efficient derivation of microglia-like cells from human pluripotent stem cells. Nat Med. 2016;22(11):1358–1367.
  • Abud EM, Ramirez RN, Martinez ES, et al. iPSC-derived human microglia-like cells to study neurological diseases. Neuron. 2017;94(2):278–293 e9.
  • Douvaras P, Sun B, Wang M, et al. Directed differentiation of human pluripotent stem cells to microglia. Stem Cell Reports. 2017;8(6):1516–1524.
  • Block ML. Neuroinflammation: modulating mighty microglia. Nat Chem Biol. 2014;10(12):988–989.
  • Dasuri K, Zhang L, Keller JN. Oxidative stress, neurodegeneration, and the balance of protein degradation and protein synthesis. Free Radic Biol Med. 2013;62:170–185.
  • DeYulia GJ Jr., Carcamo JM, Borquez-Ojeda O, et al. Hydrogen peroxide generated extracellularly by receptor-ligand interaction facilitates cell signaling. Proc Natl Acad Sci U S A. 2005;102(14):5044–5049.
  • Uttara B, Singh AV, Zamboni P, et al. Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options. Curr Neuropharmacol. 2009;7(1):65–74.
  • Surace MJ, Block ML. Targeting microglia-mediated neurotoxicity: the potential of NOX2 inhibitors. Cell Mol Life Sci. 2012;69(14):2409–2427.
  • Bedard K, Krause KH. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev. 2007;87(1):245–313.
  • Brown GC, Neher JJ. Inflammatory neurodegeneration and mechanisms of microglial killing of neurons. Mol Neurobiol. 2010;41(2–3):242–247.
  • Wang T, Qin L, Liu B, et al. Role of reactive oxygen species in LPS-induced production of prostaglandin E2 in microglia. J Neurochem. 2004;88(4):939–947.
  • Labandeira-Garcia JL, Rodriguez-Perez AI, Garrido-Gil P, et al. Brain renin-angiotensin system and microglial polarization: implications for aging and neurodegeneration. Front Aging Neurosci. 2017;3(9):129.
  • Ganong WF. What regulates the production and secretion of angiotensinogen in the brain? Front Neuroendocrinol. 1994;15(1):78–81.
  • Re RN. Tissue renin angiotensin systems. Med Clin North Am. 2004;88(1):19–38.
  • Joglar B, Rodriguez-Pallares J, Rodriguez-Perez AI, et al. The inflammatory response in the MPTP model of Parkinson’s disease is mediated by brain angiotensin: relevance to progression of the disease. J Neurochem. 2009;109(2):656–669.
  • Borrajo A, Rodriguez-Perez AI, Diaz-Ruiz C, et al. Microglial TNF-alpha mediates enhancement of dopaminergic degeneration by brain angiotensin. Glia. 2014;62(1):145–157.
  • Nguyen G, Contrepas A. Physiology and pharmacology of the (pro)renin receptor. Curr Opin Pharmacol. 2008;8(2):127–132.
  • Shan Z, Cuadra AE, Sumners C, et al. Characterization of a functional (pro)renin receptor in rat brain neurons. Exp Physiol. 2008;93(5):701–708.
  • Shi P, Grobe JL, Desland FA, et al. Direct pro-inflammatory effects of prorenin on microglia. PLoS One. 2014;9(10):e92937.
  • Cassis P, Conti S, Remuzzi G, et al. Angiotensin receptors as determinants of life span. Pflugers Arch. 2010;459(2):325–332.
  • Saavedra JM. Angiotensin II AT(1) receptor blockers as treatments for inflammatory brain disorders. Clin Sci (Lond). 2012;123(10):567–590.
  • Rodriguez-Perez AI, Borrajo A, Diaz-Ruiz C, et al. Crosstalk between insulin-like growth factor-1 and angiotensin-II in dopaminergic neurons and glial cells: role in neuroinflammation and aging. Oncotarget. 2016;7(21):30049–30067.
  • Torika N, Asraf K, Roasso E, et al. Angiotensin converting enzyme inhibitors ameliorate brain inflammation associated with microglial activation: possible implications for Alzheimer’s disease. J Neuroimmune Pharmacol. 2016;11(4):774–785.
  • Murphy S. Production of nitric oxide by glial cells: regulation and potential roles in the CNS. Glia. 2000;29(1):1–13.
  • Brown GC, Vilalta A. How microglia kill neurons. Brain Res. 2015;1628(Pt B):288–297.
  • Mander P, Brown GC. Activation of microglial NADPH oxidase is synergistic with glial iNOS expression in inducing neuronal death: a dual-key mechanism of inflammatory neurodegeneration. J Neuroinflammation. 2005;2:20.
  • Lobsiger CS, Cleveland DW. Glial cells as intrinsic components of non-cell-autonomous neurodegenerative disease. Nat Neurosci. 2007;10(11):1355–1360.
  • Noda M, Doi Y, Liang J, et al. Fractalkine attenuates excito-neurotoxicity via microglial clearance of damaged neurons and antioxidant enzyme heme oxygenase-1 expression. J Biol Chem. 2011;286(3):2308–2319.
  • Kim JH, Lee HW, Hwang J, et al. Microglia-inhibiting activity of Parkinson’s disease drug amantadine. Neurobiol Aging. 2012;33(9):2145–2159.
  • Wu HM, Tzeng NS, Qian L, et al. Novel neuroprotective mechanisms of memantine: increase in neurotrophic factor release from astroglia and anti-inflammation by preventing microglial activation. Neuropsychopharmacology. 2009;34(10):2344–2357.
  • Takeuchi H, Jin S, Wang J, et al. Tumor necrosis factor-alpha induces neurotoxicity via glutamate release from hemichannels of activated microglia in an autocrine manner. J Biol Chem. 2006;281(30):21362–21368.
  • Mizuno T, Zhang G, Takeuchi H, et al. Interferon-gamma directly induces neurotoxicity through a neuron specific, calcium-permeable complex of IFN-gamma receptor and AMPA GluR1 receptor. Faseb J. 2008;22(6):1797–1806.
  • Takeuchi H, Jin S, Suzuki H, et al. Blockade of microglial glutamate release protects against ischemic brain injury. Exp Neurol. 2008;214(1):144–146.
  • Lord B, Ameriks MK, Wang Q, et al. A novel radioligand for the ATP-gated ion channel P2X7: [3H] JNJ-54232334. Eur J Pharmacol. 2015;765:551–559.
  • Burnstock G. An introduction to the roles of purinergic signalling in neurodegeneration, neuroprotection and neuroregeneration. Neuropharmacology. 2016;104:4–17.
  • Bhattacharya A, Neff RA, Wickenden AD. The physiology, pharmacology and future of P2X7 as an analgesic drug target: hype or promise? Curr Pharm Biotechnol. 2011;12(10):1698–1706.
  • Bhattacharya A, Biber K. The microglial ATP-gated ion channel P2X7 as a CNS drug target. Glia. 2016;64(10):1772–1787.
  • Gendron FP, Chalimoniuk M, Strosznajder J, et al. P2X7 nucleotide receptor activation enhances IFN gamma-induced type II nitric oxide synthase activity in BV-2 microglial cells. J Neurochem. 2003;87(2):344–352.
  • Bartlett R, Yerbury JJ, Sluyter R. P2X7 receptor activation induces reactive oxygen species formation and cell death in murine EOC13 microglia. Mediators Inflamm. 2013;2013:271813.
  • Skaper SD, Facci L, Culbert AA, et al. P2X(7) receptors on microglial cells mediate injury to cortical neurons in vitro. Glia. 2006;54(3):234–242.
  • Cisneros-Mejorado A, Perez-Samartin A, Gottlieb M, et al. ATP signaling in brain: release, excitotoxicity and potential therapeutic targets. Cell Mol Neurobiol. 2015;35(1):1–6.
  • Sperlagh B, Illes P. P2X7 receptor: an emerging target in central nervous system diseases. Trends Pharmacol Sci. 2014;35(10):537–547.
  • Wang XH, Xie X, Luo XG, et al. Inhibiting purinergic P2X7 receptors with the antagonist brilliant blue G is neuroprotective in an intranigral lipopolysaccharide animal model of Parkinson’s disease. Mol Med Rep. 2017;15(2):768–776.
  • Takata K, Kitamura Y, Tsuchiya D, et al. High mobility group box protein-1 inhibits microglial Abeta clearance and enhances Abeta neurotoxicity. J Neurosci Res. 2004;78(6):880–891.
  • Gao HM, Zhou H, Zhang F, et al. HMGB1 acts on microglia Mac1 to mediate chronic neuroinflammation that drives progressive neurodegeneration. J Neurosci. 2011;31(3):1081–1092.
  • Huh SH, Chung YC, Piao Y, et al. Ethyl pyruvate rescues nigrostriatal dopaminergic neurons by regulating glial activation in a mouse model of Parkinson’s disease. J Immunol. 2011;187(2):960–969.
  • Shin JH, Kim ID, Kim SW, et al. Ethyl pyruvate inhibits HMGB1 phosphorylation and release by chelating calcium. Mol Med. 2015;20:649–657.
  • Mollica L, De Marchis F, Spitaleri A, et al. Glycyrrhizin binds to high-mobility group box 1 protein and inhibits its cytokine activities. Chem Biol. 2007;14(4):431–441.
  • Lee S, Nam Y, Koo JY, et al. A small molecule binding HMGB1 and HMGB2 inhibits microglia-mediated neuroinflammation. Nat Chem Biol. 2014;10(12):1055–1060.
  • Koistinaho J, Malm T, Goldsteins G. Glycogen synthase kinase-3beta: a mediator of inflammation in Alzheimer’s disease? Int J Alzheimers Dis. 2011;2011:129753.
  • Gunosewoyo H, Yu L, Munoz L, et al. Kinase targets in CNS drug discovery. Future Med Chem. 2017;9(3):303–314.
  • Yuskaitis CJ, Jope RS. Glycogen synthase kinase-3 regulates microglial migration, inflammation, and inflammation-induced neurotoxicity. Cell Signal. 2009;21(2):264–273.
  • Morales-Garcia JA, Susin C, Alonso-Gil S, et al. Glycogen synthase kinase-3 inhibitors as potent therapeutic agents for the treatment of Parkinson disease. ACS Chem Neurosci. 2013;4(2):350–360.
  • Sereno L, Coma M, Rodriguez M, et al. A novel GSK-3beta inhibitor reduces Alzheimer’s pathology and rescues neuronal loss in vivo. Neurobiol Dis. 2009;35(3):359–367.
  • Prati F, De Simone A, Bisignano P, et al. Multitarget drug discovery for Alzheimer’s disease: triazinones as BACE-1 and GSK-3beta inhibitors. Angew Chem Int Ed Engl. 2015;54(5):1578–1582.
  • Prati F, De Simone A, Armirotti A, et al. 3,4-Dihydro-1,3,5-triazin-2(1H)-ones as the first dual BACE-1/GSK-3beta fragment hits against Alzheimer’s disease. ACS Chem Neurosci. 2015;6(10):1665–1682.
  • Rhee SG, Kang SW, Jeong W, et al. Intracellular messenger function of hydrogen peroxide and its regulation by peroxiredoxins. Curr Opin Cell Biol. 2005;17(2):183–189.
  • Kang SW, Baines IC, Rhee SG. Characterization of a mammalian peroxiredoxin that contains one conserved cysteine. J Biol Chem. 1998;273(11):6303–6311.
  • Ock J, Han HS, Hong SH, et al. Obovatol attenuates microglia-mediated neuroinflammation by modulating redox regulation. Br J Pharmacol. 2010;159(8):1646–1662.
  • Ballatori N, Krance SM, Notenboom S, et al. Glutathione dysregulation and the etiology and progression of human diseases. Biol Chem. 2009;390(3):191–214.
  • Anderson ME. Glutathione: an overview of biosynthesis and modulation. Chem Biol Interact. 1998;111–112:1–14.
  • Lee M, Cho T, Jantaratnotai N, et al. Depletion of GSH in glial cells induces neurotoxicity: relevance to aging and degenerative neurological diseases. Faseb J. 2010;24(7):2533–2545.
  • Deshmukh P, Unni S, Krishnappa G, et al. The Keap1-Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases. Biophys Rev. 2017;9(1):41–56.
  • Hoing S, Rudhard Y, Reinhardt P, et al. Discovery of inhibitors of microglial neurotoxicity acting through multiple mechanisms using a stem-cell-based phenotypic assay. Cell Stem Cell. 2012;11(5):620–632.
  • Koh K, Cha Y, Kim S, et al. tBHQ inhibits LPS-induced microglial activation via Nrf2-mediated suppression of p38 phosphorylation. Biochem Biophys Res Commun. 2009;380(3):449–453.
  • Rojo AI, Innamorato NG, Martin-Moreno AM, et al. Nrf2 regulates microglial dynamics and neuroinflammation in experimental Parkinson’s disease. Glia. 2010;58(5):588–598.
  • Jazwa A, Rojo AI, Innamorato NG, et al. Pharmacological targeting of the transcription factor Nrf2 at the basal ganglia provides disease modifying therapy for experimental parkinsonism. Antioxid Redox Signal. 2011;14(12):2347–2360.
  • Neymotin A, Calingasan NY, Wille E, et al. Neuroprotective effect of Nrf2/ARE activators, CDDO ethylamide and CDDO trifluoroethylamide, in a mouse model of amyotrophic lateral sclerosis. Free Radic Biol Med. 2011;51(1):88–96.
  • Li XH, Li CY, Lu JM, et al. Allicin ameliorates cognitive deficits ageing-induced learning and memory deficits through enhancing of Nrf2 antioxidant signaling pathways. Neurosci Lett. 2012;514(1):46–50.
  • Manwani B, McCullough LD. Function of the master energy regulator adenosine monophosphate-activated protein kinase in stroke. J Neurosci Res. 2013;91(8):1018–1029.
  • Jin Q, Cheng J, Liu Y, et al. Improvement of functional recovery by chronic metformin treatment is associated with enhanced alternative activation of microglia/macrophages and increased angiogenesis and neurogenesis following experimental stroke. Brain Behav Immun. 2014;40:131–142.
  • Xu Y, Xu Y, Wang Y, et al. Telmisartan prevention of LPS-induced microglia activation involves M2 microglia polarization via CaMKKbeta-dependent AMPK activation. Brain Behav Immun. 2015;50:298–313.
  • Zhou X, Cao Y, Ao G, et al. CaMKKbeta-dependent activation of AMP-activated protein kinase is critical to suppressive effects of hydrogen sulfide on neuroinflammation. Antioxid Redox Signal. 2014;21(12):1741–1758.
  • Giri S, Nath N, Smith B, et al. 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside inhibits proinflammatory response in glial cells: a possible role of AMP-activated protein kinase. J Neurosci. 2004;24(2):479–487.
  • Lu DY, Tang CH, Chen YH, et al. Berberine suppresses neuroinflammatory responses through AMP-activated protein kinase activation in BV-2 microglia. J Cell Biochem. 2010;110(3):697–705.
  • Zhang X, Zhang X, Wang C, et al. Neuroprotection of early and short-time applying berberine in the acute phase of cerebral ischemia: up-regulated pAkt, pGSK and pCREB, down-regulated NF-kappaB expression, ameliorated BBB permeability. Brain Res. 2012;1459:61–70.
  • Haghani M, Shabani M, Tondar M. The therapeutic potential of berberine against the altered intrinsic properties of the CA1 neurons induced by Abeta neurotoxicity. Eur J Pharmacol. 2015;758:82–88.
  • Chen CC, Hung TH, Lee CY, et al. Berberine protects against neuronal damage via suppression of glia-mediated inflammation in traumatic brain injury. PLoS One. 2014;9(12):e115694.
  • Zhu XC, Jiang T, Zhang QQ, et al. Chronic metformin preconditioning provides neuroprotection via suppression of NF-kappaB-mediated inflammatory pathway in rats with permanent cerebral ischemia. Mol Neurobiol. 2015;52(1):375–385.
  • Porro C, Cianciulli A, Calvello R, et al. Reviewing the role of resveratrol as a natural modulator of microglial activities. Curr Pharm Des. 2015;21(36):5277–5291.
  • Zhang F, Liu J, Shi JS. Anti-inflammatory activities of resveratrol in the brain: role of resveratrol in microglial activation. Eur J Pharmacol. 2010;636(1–3):1–7.
  • Zhang F, Shi JS, Zhou H, et al. Resveratrol protects dopamine neurons against lipopolysaccharide-induced neurotoxicity through its anti-inflammatory actions. Mol Pharmacol. 2010;78(3):466–477.
  • Wang F, Cui N, Yang L, et al. Resveratrol rescues the impairments of hippocampal neurons stimulated by microglial over-activation in vitro. Cell Mol Neurobiol. 2015;35(7):1003–1015.
  • Chen YC, Wu JS, Tsai HD, et al. Peroxisome proliferator-activated receptor gamma (PPAR-gamma) and neurodegenerative disorders. Mol Neurobiol. 2012;46(1):114–124.
  • Pisanu A, Lecca D, Mulas G, et al. Dynamic changes in pro- and anti-inflammatory cytokines in microglia after PPAR-gamma agonist neuroprotective treatment in the MPTPp mouse model of progressive Parkinson’s disease. Neurobiol Dis. 2014;71:280–291.
  • Masciopinto F, Di Pietro N, Corona C, et al. Effects of long-term treatment with pioglitazone on cognition and glucose metabolism of PS1-KI, 3xTg-AD, and wild-type mice. Cell Death Dis. 2012;3:e448.
  • Savage JC, Jay T, Goduni E, et al. Nuclear receptors license phagocytosis by trem2+ myeloid cells in mouse models of Alzheimer’s disease. J Neurosci. 2015;35(16):6532–6543.
  • Barbiero JK, Santiago RM, Persike DS, et al. Neuroprotective effects of peroxisome proliferator-activated receptor alpha and gamma agonists in model of parkinsonism induced by intranigral 1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine. Behav Brain Res. 2014;274:390–399.
  • Song GJ, Nam Y, Jo M, et al. A novel small-molecule agonist of PPAR-gamma potentiates an anti-inflammatory M2 glial phenotype. Neuropharmacology. 2016;109:159–169.
  • Koh M, Park J, Koo JY, et al. Phenotypic screening to identify small-molecule enhancers for glucose uptake: target identification and rational optimization of their efficacy. Angew Chem Int Ed Engl. 2014;53(20):5102–5106.
  • Investigators NETiPDF-Z. Pioglitazone in early Parkinson’s disease: a phase 2, multicentre, double-blind, randomised trial. Lancet Neurol. 2015;14(8):795–803.
  • Berger SL. The complex language of chromatin regulation during transcription. Nature. 2007;447(7143):407–412.
  • Portela A, Esteller M. Epigenetic modifications and human disease. Nat Biotechnol. 2010;28(10):1057–1068.
  • Tang Y, Li T, Li J, et al. Jmjd3 is essential for the epigenetic modulation of microglia phenotypes in the immune pathogenesis of Parkinson’s disease. Cell Death Differ. 2014;21(3):369–380.
  • Cummings J, Morstorf T, Lee G. Alzheimer’s drug-development pipeline: 2016. Alzheimers Dement (N Y). 2016;2(4):222–232.
  • Song GJ, Suk K. Pharmacological modulation of functional phenotypes of microglia in neurodegenerative diseases. Front Aging Neurosci. 2017;9:139.
  • Swinney DC. Phenotypic vs. target-based drug discovery for first-in-class medicines. Clin Pharmacol Ther. 2013;93(4):299–301.
  • Swinney DC, Anthony J. How were new medicines discovered? Nat Rev Drug Discov. 2011;10(7):507–519.
  • Hu X, Leak RK, Shi Y, et al. Microglial and macrophage polarization-new prospects for brain repair. Nat Rev Neurol. 2015;11(1):56–64.
  • Komohara Y, Ohnishi K, Kuratsu J, et al. Possible involvement of the M2 anti-inflammatory macrophage phenotype in growth of human gliomas. J Pathol. 2008;216(1):15–24.
  • Biber K, Moller T, Boddeke E, et al. Central nervous system myeloid cells as drug targets: current status and translational challenges. Nat Rev Drug Discov. 2016;15(2):110–124.
  • Palmer AM, Alavijeh MS. Translational CNS medicines research. Drug Discov Today. 2012;17(19–20):1068–1078.
  • Gribkoff VK, Kaczmarek LK. The need for new approaches in CNS drug discovery: why drugs have failed, and what can be done to improve outcomes. Neuropharmacology. 2017;120:11–19.
  • Galatro TF, Holtman IR, Lerario AM, et al. Transcriptomic analysis of purified human cortical microglia reveals age-associated changes. Nat Neurosci. 2017;20(8):1162–1171.
  • Gosselin D, Skola D, Coufal NG, et al. An environment-dependent transcriptional network specifies human microglia identity. Science. 2017;356:6344.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.