Regulation of microglial activation in stroke

Acta Pharmacologica Sinica

Volumn 38, Issue 4, 2017, Pages 445-458

  Zhao, Shou Cai ^a   Ma, Ling Song ^a   Chu, Zhao Hu ^a   Xu, Heng ^a   Wu, Wen Qian ^a   Liu, Fudong ^b  

^a WANNAN MEDICAL COLLEGE   (China)

^b UNIVERSITY OF TEXAS MEDICAL SCHOOL   (United States)

Author keywords

brain; cerebral ischemia; cytokines; macrophage; microglia; microglia neuron interaction; neuroinflammation

Indexed keywords

CD200 ANTIGEN; CD200 RECEPTOR; CXCL3 CHEMOKINE; GRANULOCYTE COLONY STIMULATING FACTOR; HISTAMINE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; INTERFERON CONSENSUS SEQUENCE BINDING PROTEIN; INTERFERON REGULATORY FACTOR; INTERFERON REGULATORY FACTOR 1; INTERFERON REGULATORY FACTOR 2; INTERFERON REGULATORY FACTOR 3; INTERFERON REGULATORY FACTOR 4; INTERFERON REGULATORY FACTOR 5; INTERFERON REGULATORY FACTOR 7; JUMONJI DOMAIN CONTAINING PROTEIN 3; MICRORNA; MITOGEN ACTIVATED PROTEIN KINASE; NEUTROPHIL GELATINASE ASSOCIATED LIPOCALIN; NOTCH RECEPTOR; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR; PROGRAMMED DEATH 1 RECEPTOR; PROTEIN; PROTEIN P53; SIALIC ACID BINDING IMMUNOGLOBULIN LIKE LECTIN; SUBSTANCE P; TOLL LIKE RECEPTOR; TRIGGERING RECEPTOR EXPRESSED ON MYELOID CELLS 2; UNCLASSIFIED DRUG; AUTACOID; IMMUNOGLOBULIN RECEPTOR; LEUKOCYTE ANTIGEN;

BONE MARROW; CELL ACTIVATION; CELL INTERACTION; CEREBROVASCULAR ACCIDENT; GLIA CELL; HUMAN; MACROPHAGE; MACROPHAGE ACTIVATION; MESENCHYMAL STROMA CELL; MICROGLIA; NERVE CELL; NONHUMAN; REVIEW; ANIMAL; ASTROCYTE; BRAIN ISCHEMIA; IMMUNOLOGY; INFLAMMATION; METABOLISM; OLIGODENDROGLIA; PATHOLOGY; SIGNAL TRANSDUCTION;

ANIMALS; ANTIGENS, CD; ASTROCYTES; BRAIN ISCHEMIA; HUMANS; INFLAMMATION; INFLAMMATION MEDIATORS; INTERFERON REGULATORY FACTORS; MACROPHAGE ACTIVATION; MICROGLIA; MICRORNAS; NEURONS; OLIGODENDROGLIA; RECEPTOR CROSS-TALK; RECEPTORS, IMMUNOLOGIC; SIGNAL TRANSDUCTION; STROKE;

EID: 85016948449     PISSN: 16714083     EISSN: 17457254     Source Type: Journal    
DOI: 10.1038/aps.2016.162     Document Type: Review

References (157)

1. Perego C, Fumagalli S, De Simoni MG. Temporal pattern of expression and colocalization of microglia/macrophage phenotype markers following brain ischemic injury in mice. J Neuroinfammation 2011; 8: 174.
2. 11C]vinpocetine. J Neurol Sci 2012; 320: 110-7.
3. Perego C, Fumagalli S, De Simoni MG. Three-dimensional confocal analysis of microglia/macrophage markers of polarization in experimental brain injury. J Vis Exp 2013. Doi: 10.3791/50605.
4. Kreutzberg GW. Microglia: a sensor for pathological events in the CNS. Trends Neurosci 1996; 19: 312-8.
5. Perry VH, Nicoll JA, Holmes C. Microglia in neurodegenerative disease. Nat Rev Neurol 2010; 6: 193-201.
6. Chan WY, Kohsaka S, Rezaie P. The origin and cell lineage of microg-lia: new concepts. Brain Res Rev 2007; 53: 344-54.
7. Kettenmann H, Hanisch UK, Noda M, Verkhratsky A. Physiology of microglia. Physiol Rev 2011; 91: 461-553.
8. Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, et al. ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 2005; 8: 752-8.
9. Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 2005; 308: 1314-8.
10. Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 2012; 74: 691-705.
11. Paolicelli RC, Gross CT. Microglia in development: linking brain wiring to brain environment. Neuron Glia Biol 2011; 7: 77-83.
12. Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 2010; 330: 841-5.
13. Patel AR, Ritzel R, McCullough LD, Liu F. Microglia and ischemic stroke: a double-edged sword. Int J Physiol Pathophysiol Pharmacol 2013; 5: 73-90.
14. Galea J, Cruickshank G, Teeling JL, Boche D, Garland P, Perry VH, et al. The intrathecal CD163-haptoglobin-hemoglobin scavenging system in subarachnoid hemorrhage. J Neurochem 2012; 121: 785-92.
15. Hu X, Li P, Guo Y, Wang H, Leak RK, Chen S, et al. Microglia/macro-phage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia. Stroke 2012; 43: 3063-70.
16. Nathan CF, Murray HW, Wiebe ME, Rubin BY. Identifcation of inter-feron-gamma as the lymphokine that activates human macrophage oxidative metabolism and antimicrobial activity. J Exp Med 1983; 158: 670-89.
17. Cao L, He C. Polarization of macrophages and microglia in infamma-tory demyelination. Neurosci Bull 2013; 29: 189-98.
18. Martinez FO, Helming L, Gordon S. Alternative activation of macro-phages: an immunologic functional perspective. Annu Rev Immunol 2009; 27: 451-83.
19. Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol 2005; 5: 953-64.
20. Mills CD, Kincaid K, Alt JM, Heilman MJ, Hill AM. M-1/M-2 macro-phages and the Th1/Th2 paradigm. J Immunol 2000; 164: 6166-73.
21. Gordon S. Alternative activation of macrophages. Nat Rev Immunol 2003; 3: 23-35.
22. Varnum MM, Ikezu T. The classifcation of microglial activation phe-notypes on neurodegeneration and regeneration in Alzheimer's disease brain. Arch Immunol Ther Exp (Warsz) 2012; 60: 251-66.
23. Jimenez S, Baglietto-Vargas D, Caballero C, Moreno-Gonzalez I, Torres M, Sanchez-Varo R, et al. Infammatory response in the hippocampus of PS1M146L/APP751SL mouse model of Alzheimer's disease: age-dependent switch in the microglial phenotype from alternative to classic. J Neurosci 2008; 28: 11650-61.
24. Perry VH, Teeling J. Microglia and macrophages of the central nervous system: the contribution of microglia priming and systemic infammation to chronic neurodegeneration. Semin Immunopathol 2013; 35: 601-12.
25. Lehnardt S. Innate immunity and neuroinfammation in the CNS: the role of microglia in Toll-like receptor-mediated neuronal injury. Glia 2010; 58: 253-63.
26. Jack CS, Arbour N, Manusow J, Montgrain V, Blain M, McCrea E, et al. TLR signaling tailors innate immune responses in human microglia and astrocytes. J Immunol 2005; 175: 4320-30.
27. Henn A, Kirner S, Leist M. TLR2 hypersensitivity of astrocytes as functional consequence of previous infammatory episodes. J Immunol 2011; 186: 3237-47.
28. Phulwani NK, Esen N, Syed MM, Kielian T. TLR2 expression in astro-cytes is induced by TNF-alpha-and NF-kappa B-dependent pathways. J Immunol 2008; 181: 3841-9.
29. Goethals S, Ydens E, Timmerman V, Janssens S. Toll-like receptor expression in the peripheral nerve. Glia 2010; 58: 1701-9.
30. Tang SC, Arumugam TV, Xu X, Cheng A, Mughal MR, Jo DG, et al. Pivotal role for neuronal Toll-like receptors in ischemic brain injury and functional defcits. Proc Natl Acad Sci USA 2007; 104: 13798-803.
31. Olson JK, Miller SD. Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J Immunol 2004; 173: 3916-24.
32. Kopp E, Medzhitov R. Recognition of microbial infection by Toll-like receptors. Curr Opin Immunol 2003; 15: 396-401.
33. Beutler B. Inferences, questions and possibilities in Toll-like receptor signalling. Nature 2004; 430: 257-63.
34. Yamamoto M, Takeda K, Akira S. TIR domain-containing adaptors defne the specifcity of TLR signaling. Mol Immunol 2004; 40: 861-8.
35. Lim H, Kim D, Lee SJ. Toll-like receptor 2 mediates peripheral nerve injury-induced NADPH oxidase 2 expression in spinal cord microglia. J Biol Chem 2013; 288: 7572-9.
36. Lv M, Liu Y, Zhang J, Sun L, Liu Z, Zhang S, et al. Roles of infam-mation response in microglia cell through toll-like receptors 2/inter-leukin-23/interleukin-17 pathway in cerebral ischemia/reperfusion injury. Neuroscience 2011; 176: 162-72.
37. Stirling DP, Cummins K, Mishra M, Teo W, Yong VW, Stys P. Toll-like receptor 2-mediated alternative activation of microglia is protective after spinal cord injury. Brain 2014; 137: 707-23.
38. Jiang R, Ye J, Zhu B, Song Y, Chen H, Cao S. Roles of TLR3 and RIG-I in mediating the infammatory response in mouse microglia following Japanese encephalitis virus infection. J Immunol Res 2014; 2014: 787023.
39. + T cells by Toll-like receptor 3-activated human microglia. J Neuropathol Exp Neurol 2007; 66: 848-59.
40. Jung DY, Lee H, Jung BY, Ock J, Lee MS, Lee WH, et al. TLR4, but not TLR2, signals autoregulatory apoptosis of cultured microglia: a critical role of IFN-beta as a decision maker. J Immunol 2005; 174: 6467-76.
41. Ziegler G, Harhausen D, Schepers C, Hoffmann O, Rohr C, Prinz V, et al. TLR2 has a detrimental role in mouse transient focal cerebral ischemia. Biochem Biophys Res Commun 2007; 359: 574-9.
42. Cao CX, Yang QW, Lv FL, Cui J, Fu HB, Wang JZ. Reduced cerebral ischemia-reperfusion injury in Toll-like receptor 4 defcient mice. Bio-chem Biophys Res Commun 2007; 353: 509-14.
43. Hua F, Ma J, Ha T, Kelley JL, Kao RL, Schweitzer JB, et al. Differential roles of TLR2 and TLR4 in acute focal cerebral ischemia/reperfusion injury in mice. Brain Res 2009; 1262: 100-8.
44. Kilic U, Kilic E, Matter CM, Bassetti CL, Hermann DM. TLR-4 defciency protects against focal cerebral ischemia and axotomy-induced neurodegeneration. Neurobiol Dis 2008; 31: 33-40.
45. Zhu J, Qu C, Lu X, Zhang S. Activation of microglia by histamine and substance P. Cell Physiol Biochem 2014; 34: 768-80.
46. Pannell M, Szulzewsky F, Matyash V, Wolf SA, Kettenmann H. The subpopulation of microglia sensitive to neurotransmitters/neurohor-mones is modulated by stimulation with LPS, interferon-gamma, and IL-4. Glia 2014; 62: 667-79.
47. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 2008; 26: 677-704.
48. Okazaki T, Honjo T. The PD-1-PD-L pathway in immunological tolerance. Trends Immunol 2006; 27: 195-201.
49. Salama AD, Chitnis T, Imitola J, Ansari MJ, Akiba H, Tushima F, et al. Critical role of the programmed death-1 (PD-1) pathway in regulation of experimental autoimmune encephalomyelitis. J Exp Med 2003; 198: 71-8.
50. Yao AH, Liu FF, Chen K, Tang L, Liu L, Zhang K, et al. Programmed death 1 defciency induces the polarization of macrophages/microg-lia to the M1 phenotype after spinal cord injury in mice. Neurothera-peutics 2014; 11: 636-50.
51. Kjeldsen L, Cowland JB, Borregaard N. Human neutrophil gelatinase-associated lipocalin and homologous proteins in rat and mouse. Bio-chim Biophys Acta 2000; 1482: 272-83.
52. Kehrer JP. Lipocalin-2: pro-or anti-apoptotic? Cell Biol Toxicol 2010; 26: 83-9.
53. Yang J, Bielenberg DR, Rodig SJ, Doiron R, Clifton MC, Kung AL, et al. Lipocalin 2 promotes breast cancer progression. Proc Natl Acad Sci USA 2009; 106: 3913-8.
54. Flo TH, Smith KD, Sato S, Rodriguez DJ, Holmes MA, Strong RK, et al. Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature 2004; 432: 917-21.
55. Nielsen BS, Borregaard N, Bundgaard JR, Timshel S, Sehested M, Kjeldsen L. Induction of NGAL synthesis in epithelial cells of human colorectal neoplasia and infammatory bowel diseases. Gut 1996; 38: 414-20.
56. Jang E, Lee S, Kim JH, Kim JH, Seo JW, Lee WH, et al. Secreted protein lipocalin-2 promotes microglial M1 polarization. FASEB J 2013; 27: 1176-90.
57. Han Q, Liu S, Li Z, Hu F, Zhang Q, Zhou M, et al. DCPIB, a potent volume-regulated anion channel antagonist, attenuates microglia-mediated infammatory response and neuronal injury following focal cerebral ischemia. Brain Res 2014; 1542: 176-85.
58. Zhou XM, Cao YJ, Ao GZ, Hu LF, Liu H, Wu J, et al. CaMKK beta-dependent activation of amp-activated protein kinase is critical to sup-pressive effects of hydrogen sulfde on neuroinfammation. Antioxid Redox Signal 2014; 21: 1741-58.
59. Veremeyko T, Siddiqui S, Sotnikov I, Yung A, Ponomarev ED. IL-4/IL-13-dependent and independent expression of miR-124 and its contribution to M2 phenotype of monocytic cells in normal conditions and during allergic infammation. PLoS One 2013; 8: e81774.
60. Zhao H, Wang J, Gao L, Wang R, Liu X, Gao Z, et al. MiRNA-424 protects against permanent focal cerebral ischemia injury in mice involving suppressing microglia activation. Stroke 2013; 44: 1706-13.
61. Jadhav SP, Kamath SP, Choolani M, Lu J, Dheen ST. microRNA-200b modulates microglia-mediated neuroinflammation via the cJun/MAPK pathway. J Neurochem 2014; 130: 388-401.
62. Liu HC, Zheng MH, Du YL, Wang L, Kuang F, Qin HY, et al. N9 mi-croglial cells polarized by LPS and IL4 show differential responses to secondary environmental stimuli. Cell Immunol 2012; 278: 84-90.
63. Wei Z, Chigurupati S, Arumugam TV, Jo DG, Li H, Chan SL. Notch activation enhances the microglia-mediated infammatory response associated with focal cerebral ischemia. Stroke 2011; 42: 2589-94.
64. Yin J, Li H, Feng C, Zuo Z. Inhibition of brain ischemia-caused notch activation in microglia may contribute to isofurane postconditioning-induced neuroprotection in male rats. CNS Neurol Disord Drug Targets 2014; 13: 718-32.
65. Escalante CR, Yie J, Thanos D, Aggarwal AK. Structure of IRF-1 with bound DNA reveals determinants of interferon regulation. Nature 1998; 391: 103-6.
66. Negishi H, Fujita Y, Yanai H, Sakaguchi S, Ouyang X, Shinohara M, et al. Evidence for licensing of IFN-gamma-induced IFN regulatory factor 1 transcription factor by MyD88 in Toll-like receptor-dependent gene induction program. Proc Natl Acad Sci USA 2006; 103: 15136-41.
67. Elser B, Lohoff M, Kock S, Giaisi M, Kirchhoff S, Krammer PH, et al. IFN-gamma represses IL-4 expression via IRF-1 and IRF-2. Immunity 2002; 17: 703-12.
68. Wang Y, John R, Chen J, Richardson JA, Shelton JM, Bennett M, et al. IRF-1 promotes infammation early after ischemic acute kidney injury. J Am Soc Nephrol 2009; 20: 1544-55.
69. Iadecola C, Salkowski CA, Zhang F, Aber T, Nagayama M, Vogel SN, et al. The transcription factor interferon regulatory factor 1 is expressed after cerebral ischemia and contributes to ischemic brain injury. J Exp Med 1999; 189: 719-27.
70. Alexander M, Forster C, Sugimoto K, Clark HB, Vogel S, Ross ME, et al. Interferon regulatory factor-1 immunoreactivity in neurons and infammatory cells following ischemic stroke in rodents and humans. Acta Neuropathol 2003; 105: 420-4.
71. Blanco JC, Contursi C, Salkowski CA, DeWitt DL, Ozato K, Vogel SN. Interferon regulatory factor (IRF)-1 and IRF-2 regulate interferon gamma-dependent cyclooxygenase 2 expression. J Exp Med 2000; 191: 2131-44.
72. Oshima S, Nakamura T, Namiki S, Okada E, Tsuchiya K, Okamoto R, et al. Interferon regulatory factor 1 (IRF-1) and IRF-2 distinctively up-regulate gene expression and production of interleukin-7 in human intestinal epithelial cells. Mol Cell Biol 2004; 24: 6298-310.
73. Cuesta N, Salkowski CA, Thomas KE, Vogel SN. Regulation of li-popolysaccharide sensitivity by IFN regulatory factor-2. J Immunol 2003; 170: 5739-47.
74. Han KJ, Jiang L, Shu HB. Regulation of IRF2 transcriptional activity by its sumoylation. Biochem Biophys Res Commun 2008; 372: 772-8.
75. Nhu QM, Cuesta N, Vogel SN. Transcriptional regulation of lipopoly-saccharide (LPS)-induced Toll-like receptor (TLR) expression in mu-rine macrophages: role of interferon regulatory factors 1 (IRF-1) and 2 (IRF-2). J Endotoxin Res 2006; 12: 285-95.
76. Gunthner R, Anders HJ. Interferon-regulatory factors determine mac-rophage phenotype polarization. Mediators Inflamm 2013; 2013: 731023.
77. Tarassishin L, Suh HS, Lee SC. Interferon regulatory factor 3 plays an anti-infammatory role in microglia by activating the PI3K/Akt pathway. J Neuroinfammation 2011; 8: 187.
78. Tarassishin L, Loudig O, Bauman A, Shaft-Zagardo B, Suh HS, Lee SC. Interferon regulatory factor 3 inhibits astrocyte inflammatory gene expression through suppression of the proinfammatory miR-155 and miR-155∗. Glia 2011; 59: 1911-22.
79. Xu WD, Pan HF, Ye DQ, Xu Y. Targeting IRF4 in autoimmune diseases. Autoimmun Rev 2012; 11: 918-24.
80. El Chartouni C, Schwarzfischer L, Rehli M. Interleukin-4 induced interferon regulatory factor (Irf) 4 participates in the regulation of alternative macrophage priming. Immunobiology 2010; 215: 821-5.
81. Eguchi J, Kong X, Tenta M, Wang X, Kang S, Rosen ED. Interferon regulatory factor 4 regulates obesity-induced infammation through regulation of adipose tissue macrophage polarization. Diabetes 2013; 62: 3394-403.
82. Guo S, Li ZZ, Jiang DS, Lu YY, Liu Y, Gao L, et al. IRF4 is a novel mediator for neuronal survival in ischaemic stroke. Cell Death Differ 2014; 21: 888-903.
83. Korczeniewska J, Barnes BJ. The COP9 signalosome interacts with and regulates interferon regulatory factor 5 protein stability. Mol Cell Biol 2013; 33: 1124-38.
84. Lawrence T, Natoli G. Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nat Rev Immunol 2011; 11: 750-61.
85. Tanaka T, Murakami K, Bando Y, Yoshida S. Interferon regulatory factor 7 participates in the M1-like microglial polarization switch. Glia 2015; 63: 595-610.
86. Minten C, Terry R, Deffrasnes C, King NJ, Campbell IL. IFN regulatory factor 8 is a key constitutive determinant of the morphological and molecular properties of microglia in the CNS. PLoS One 2012; 7: e49851.
87. Horiuchi M, Wakayama K, Itoh A, Kawai K, Pleasure D, Ozato K, et al. Interferon regulatory factor 8/interferon consensus sequence binding protein is a critical transcription factor for the physiological phenotype of microglia. J Neuroinfammation 2012; 9: 227.
88. Xiang M, Wang L, Guo S, Lu YY, Lei H, Jiang DS, et al. Interferon regulatory factor 8 protects against cerebral ischaemic-reperfusion injury. J Neurochem 2014; 129: 988-1001.
89. Masuda T, Tsuda M, Yoshinaga R, Tozaki-Saitoh H, Ozato K, Tamura T, et al. IRF8 is a critical transcription factor for transforming microglia into a reactive phenotype. Cell Rep 2012; 1: 334-40.
90. Xu H, Zhu J, Smith S, Foldi J, Zhao B, Chung AY, et al. Notch-RBP-J signaling regulates the transcription factor IRF8 to promote infam-matory macrophage polarization. Nat Immunol 2012; 13: 642-50.
91. Yoshida Y, Yoshimi R, Yoshii H, Kim D, Dey A, Xiong H, et al. The transcription factor IRF8 activates integrin-mediated TGF-beta signaling and promotes neuroinfammation. Immunity 2014; 40: 187-98.
92. Jayadev S, Nesser NK, Hopkins S, Myers SJ, Case A, Lee RJ, et al. Transcription factor p53 influences microglial activation phenotype. Glia 2011; 59: 1402-13.
93. Davenport CM, Sevastou IG, Hooper C, Pocock JM. Inhibiting p53 pathways in microglia attenuates microglial-evoked neurotoxicity following exposure to Alzheimer peptides. J Neurochem 2010; 112: 552-63.
94. Tu YF, Lu PJ, Huang CC, Ho CJ, Chou YP. Moderate dietary restriction reduces p53-mediated neurovascular damage and microglia activation after hypoxic ischemia in neonatal brain. Stroke 2012; 43: 491-8.
95. Tang Y, Li T, Li J, Yang J, Liu H, Zhang XJ, 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: 369-80.
96. Satoh T, Takeuchi O, Vandenbon A, Yasuda K, Tanaka Y, Kumagai Y, et al. The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection. Nat Immunol 2010; 11: 936-44.
97. Satoh N, Shimatsu A, Himeno A, Sasaki Y, Yamakage H, Yamada K, et al. Unbalanced M1/M2 phenotype of peripheral blood monocytes in obese diabetic patients: effect of pioglitazone. Diabetes Care 2010; 33: e7.
98. Pisanu A, Lecca D, Mulas G, Wardas J, Simbula G, Spiga S, et al. Dynamic changes in pro-and anti-infammatory cytokines in microglia after PPAR-gamma agonist neuroprotective treatment in the MPTPp mouse model of progressive Parkinson's disease. Neurobiol Dis 2014; 71: 280-91.
99. Mou CZ, Liu B, Wang M, Jiang M, Han T. PGC-1-Related Coactivator (PRC) Is an Important Regulator of Microglia M2 Polarization. J Mol Neurosci 2015; 55: 69-75.
100. Pan J, Jin JL, Ge HM, Yin KL, Chen X, Han LJ, et al. Malibatol A regulates microglia M1/M2 polarization in experimental stroke in a PPAR gamma-dependent manner. J Neuroinfammation 2015; 12: 51.
101. Guo Y, Zhang H, Yang J, Liu S, Bing L, Gao J, et al. Granulocyte colony-stimulating factor improves alternative activation of microglia under microenvironment of spinal cord injury. Neuroscience 2013; 238: 1-10.
102. Hegyi B, Kornyei Z, Ferenczi S, Fekete R, Kudlik G, Kovacs KJ, et al. Regulation of mouse microglia activation and effector functions by bone marrow-derived mesenchymal stem cells. Stem Cells Develop 2014; 23: 2600-12.
103. Ohtaki H, Ylostalo JH, Foraker JE, Robinson AP, Reger RL, Shioda S, et al. Stem/progenitor cells from bone marrow decrease neuronal death in global ischemia by modulation of infammatory/immune responses. Proc Natl Acad Sci USA 2008; 105: 14638-43.
104. Zanier ER, Pischiutta F, Riganti L, Marchesi F, Turola E, Fumagalli S, et al. Bone marrow mesenchymal stromal cells drive protective M2 microglia polarization after brain trauma. Neurotherapeutics 2014; 11: 679-95.
105. Ferrini F, De Koninck Y. Microglia control neuronal network excitability via BDNF signalling. Neural Plast 2013; 2013: 429815.
106. Biber K, Vinet J, Boddeke HW. Neuron-microglia signaling: chemo-kines as versatile messengers. J Neuroimmunol 2008; 198: 69-74.
107. de Haas AH, van Weering HR, de Jong EK, Boddeke HW, Biber KP. Neuronal chemokines: versatile messengers in central nervous system cell interaction. Mol Neurobiol 2007; 36: 137-51.
108. Yi MH, Zhang E, Kang JW, Shin YN, Byun JY, Oh SH, et al. Expression of CD200 in alternative activation of microglia following an excitotoxic lesion in the mouse hippocampus. Brain Res 2012; 1481: 90-6.
109. Shrivastava K, Gonzalez P, Acarin L. The immune inhibitory complex CD200/CD200R is developmentally regulated in the mouse brain. J Comp Neurol 2012; 520: 2657-75.
110. Denieffe S, Kelly RJ, McDonald C, Lyons A, Lynch MA. Classical activation of microglia in CD200-deficient mice is a consequence of blood brain barrier permeability and infltration of peripheral cells. Brain Behav Immun 2013; 34: 86-97.
111. Hernangomez M, Mestre L, Correa FG, Loria F, Mecha M, Inigo PM, et al. CD200-CD200R1 interaction contributes to neuroprotective effects of anandamide on experimentally induced infammation. Glia 2012; 60: 1437-50.
112. Chitnis T, Imitola J, Wang Y, Elyaman W, Chawla P, Sharuk M, et al. Elevated neuronal expression of CD200 protects Wlds mice from infammation-mediated neurodegeneration. Am J Pathol 2007; 170: 1695-712.
113. Cox FF, Carney D, Miller AM, Lynch MA. CD200 fusion protein decreases microglial activation in the hippocampus of aged rats. Brain Behav Immun 2012; 26: 789-96.
114. Maciejewski-Lenoir D, Chen S, Feng L, Maki R, Bacon KB. Characterization of fractalkine in rat brain cells: migratory and activation signals for CX3CR-1-expressing microglia. J Immunol 1999; 163: 1628-35.
115. Tang Z, Gan Y, Liu Q, Yin JX, Shi J, Shi FD. CX3CR1 defciency suppresses activation and neurotoxicity of microglia/macrophage in experimental ischemic stroke. J Neuroinfammation 2014; 11: 26.
116. Sun JL, Xiao C, Lu B, Zhang J, Yuan XZ, Chen W, et al. CX3CL1/CX3CR1 regulates nerve injury-induced pain hypersensitivity through the ERK5 signaling pathway. J Neurosci Res 2013; 91: 545-53.
117. Iadecola C, Anrather J. The immunology of stroke: from mechanisms to translation. Nat Med 2011; 17: 796-808.
118. Cardona AE, Pioro EP, Sasse ME, Kostenko V, Cardona SM, Dijkstra IM, et al. Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci 2006; 9: 917-24.
119. Taylor RA, Sansing LH. Microglial responses after ischemic stroke and intracerebral hemorrhage. Clin Dev Immunol 2013; 2013: 746068.
120. Takahashi K, Rochford CD, Neumann H. Clearance of apoptotic neurons without infammation by microglial triggering receptor expressed on myeloid cells-2. J Exp Med 2005; 201: 647-57.
121. Daws MR, Sullam PM, Niemi EC, Chen TT, Tchao NK, Seaman WE. Pattern recognition by TREM-2: binding of anionic ligands. J Immunol 2003; 171: 594-9.
122. Kawabori M, Kacimi R, Kauppinen T, Calosing C, Kim JY, Hsieh CL, et al. Triggering receptor expressed on myeloid cells 2 (TREM2) def-ciency attenuates phagocytic activities of microglia and exacerbates ischemic damage in experimental stroke. J Neurosci 2015; 35: 3384-96.
123. Sieber MW, Jaenisch N, Brehm M, Guenther M, Linnartz-Gerlach B, Neumann H, et al. Attenuated infammatory response in triggering receptor expressed on myeloid cells 2 (TREM2) knock-out mice following stroke. PLoS One 2013; 8: e52982.
124. Schmid CD, Sautkulis LN, Danielson PE, Cooper J, Hasel KW, Hilbush BS, et al. Heterogeneous expression of the triggering receptor expressed on myeloid cells-2 on adult murine microglia. J Neurochem 2002; 83: 1309-20.
125. Stefano L, Racchetti G, Bianco F, Passini N, Gupta RS, Panina Bordi-gnon P, et al. The surface-exposed chaperone, Hsp60, is an agonist of the microglial TREM2 receptor. J Neurochem 2009; 110: 284-94.
126. Varki A, Angata T. Siglecs-the major subfamily of I-type lectins. Gly-cobiology 2006; 16: 1R-27R.
127. Pillai S, Netravali IA, Cariappa A, Mattoo H. Siglecs and immune regulation. Annu Rev Immunol 2012; 30: 357-92.
128. Crocker PR, Paulson JC, Varki A. Siglecs and their roles in the immune system. Nat Rev Immunol 2007; 7: 255-66.
129. Foussias G, Taylor SM, Yousef GM, Tropak MB, Ordon MH, Diamandis EP. Cloning and molecular characterization of two splice variants of a new putative member of the Siglec-3-like subgroup of Siglecs. Bio-chem Biophys Res Commun 2001; 284: 887-99.
130. Jellusova J, Nitschke L. Regulation of B cell functions by the sialic acid-binding receptors siglec-G and CD22. Front Immunol 2011; 2: 96.
131. Mott RT, Ait-Ghezala G, Town T, Mori T, Vendrame M, Zeng J, et al. Neuronal expression of CD22: novel mechanism for inhibiting microg-lial proinfammatory cytokine production. Glia 2004; 46: 369-79.
132. Wang Y, Neumann H. Alleviation of neurotoxicity by microglial human Siglec-11. J Neurosci 2010; 30: 3482-8.
133. Lajaunias F, Dayer JM, Chizzolini C. Constitutive repressor activity of CD33 on human monocytes requires sialic acid recognition and phosphoinositide 3-kinase-mediated intracellular signaling. Eur J Immunol 2005; 35: 243-51.
134. Petrovic-Djergovic D, Goonewardena SN, Pinsky DJ. Inflammatory disequilibrium in stroke. Circ Res 2016; 119: 142-58.
135. Mu S, Liu B, Ouyang L, Zhan M, Chen S, Wu J, et al. Characteristic changes of astrocyte and microglia in rat striatum induced by 3-NP and MCAO. Neurochem Res 2016; 41: 707-14.
136. Rohl C, Lucius R, Sievers J. The effect of activated microglia on as-trogliosis parameters in astrocyte cultures. Brain Res 2007; 1129: 43-52.
137. Siglienti I, Chan A, Kleinschnitz C, Jander S, Toyka KV, Gold R, et al. Downregulation of transforming growth factor-beta2 facilitates infammation in the central nervous system by reciprocal astrocyte/microglia interactions. J Neuropathol Exp Neurol 2007; 66: 47-56.
138. Lana D, Melani A, Pugliese AM, Cipriani S, Nosi D, Pedata F, et al. The neuron-astrocyte-microglia triad in a rat model of chronic cerebral hypoperfusion: protective effect of dipyridamole. Front Aging Neuro sci 2014; 6: 322.
139. Quintas C, Pinho D, Pereira C, Saraiva L, Goncalves J, Queiroz G. Mi-croglia P2Y(6) receptors mediate nitric oxide release and astrocyte apoptosis. J Neuroinfammation 2014; 11: 141.
140. Lian H, Litvinchuk A, Chiang AC, Aithmitti N, Jankowsky JL, Zheng H. Astrocyte-microglia cross talk through complement activation modulates amyloid pathology in mouse models of Alzheimer's disease. J Neurosci 2016; 36: 577-89.
141. Zajicek JP, Wing M, Scolding NJ, Compston DA. Interactions between oligodendrocytes and microglia. A major role for complement and tumour necrosis factor in oligodendrocyte adherence and killing. Brain 1992; 115: 1611-31.
142. Peterson JW, Bo L, Mork S, Chang A, Ransohoff RM, Trapp BD. VCAM-1-positive microglia target oligodendrocytes at the border of multiple sclerosis lesions. J Neuropathol Exp Neurol 2002; 61: 539-46.
143. Miller BA, Crum JM, Tovar CA, Ferguson AR, Bresnahan JC, Beattie MS. Developmental stage of oligodendrocytes determines their response to activated microglia in vitro. J Neuroinfammation 2007; 4: 28.
144. Mabuchi T, Kitagawa K, Ohtsuki T, Kuwabara K, Yagita Y, Yanagihara T, et al. Contribution of microglia/macrophages to expansion of infarction and response of oligodendrocytes after focal cerebral ischemia in rats. Stroke 2000; 31: 1735-43.
145. Jin Q, Cheng J, Liu Y, Wu J, Wang X, Wei S, 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: 131-42.
146. Zhu XC, Jiang T, Zhang QQ, Cao L, Tan MS, Wang HF, et al. Chronic metformin preconditioning provides neuroprotection via suppression of NF-kappaB-mediated infammatory pathway in rats with permanent cerebral ischemia. Mol Neurobiol 2015; 52: 375-85.
147. Zieden B, Olsson AG. The role of statins in the prevention of ischemic stroke. Curr Atheroscler Rep 2005; 7: 364-8.
148. Churchward MA, Todd KG. Statin treatment affects cytokine release and phagocytic activity in primary cultured microglia through two separable mechanisms. Mol Brain 2014; 7: 85.
149. Jung YS, Park JH, Kim H, Kim SY, Hwang JY, Hong KW, et al. Probucol inhibits LPS-induced microglia activation and ameliorates brain ischemic injury in normal and hyperlipidemic mice. Acta Pharmacol Sin 2016; 37: 1031-44.
150. Lopes RS, Cardoso MM, Sampaio AO, Barbosa MS Jr, Souza CC, DA Silva MC, et al. Indomethacin treatment reduces microglia activation and increases numbers of neuroblasts in the subventricular zone and ischaemic striatum after focal ischaemia. J Biosci 2016; 41: 381-94.
151. Samanta J, Alden T, Gobeske K, Kan L, Kessler JA. Noggin protects against ischemic brain injury in rodents. Stroke 2010; 41: 357-62.
152. Shin JA, Lim SM, Jeong SI, Kang JL, Park EM. Noggin improves ischemic brain tissue repair and promotes alternative activation of microglia in mice. Brain Behav Immun 2014; 40: 143-54.
153. Yang C, Yu L, Kong L, Ma R, Zhang J, Zhu Q, et al. Pyrroloquinoline quinone (PQQ) inhibits lipopolysaccharide induced inflammation in part via downregulated NF-kappaB and p38/JNK activation in microglial and attenuates microglia activation in lipopolysaccharide treatment mice. PLoS One 2014; 9: e109502.
154. Huang L, Li G, Feng X, Wang L. 15d-PGJ2 reduced microglia activation and alleviated neurological deficit of ischemic reperfusion in diabetic rat model. Biomed Res Int 2015; 2015: 864509.
155. Guglielmetti C, Le Blon D, Santermans E, Salas-Perdomo A, Daans J, De Vocht N, et al. Interleukin-13 immune gene therapy prevents CNS inflammation and demyelination via alternative activation of microglia and macrophages. Glia 2016; 64: 2181-200.
156. Gregersen R, Lambertsen K, Finsen B. Microglia and macrophages are the major source of tumor necrosis factor in permanent middle cerebral artery occlusion in mice. J Cereb Blood Flow Metab 2000; 20: 53-65.
157. Chen Y, Won SJ, Xu Y, Swanson RA. Targeting microglial activation in stroke therapy: pharmacological tools and gender effects. Curr Med Chem 2014; 21: 2146-55.