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A análise da expressão gênica de marcadores associados aos fenótipos de ativação da micróglia (CD163 e IL1B) em gliomas humanos revelou maiores níveis de CD163, um marcador característico do fenótipo anti-inflamatório da micróglia, em amostras de astrocitoma. O mesmo foi verdade para os subtipos Clássico e Mesenquimal de GBM. Podemos concluir que esse aumento está associado a um pior prognóstico, como foi demonstrado para o subtipo Clássico. No entanto, essas análises demostraram grande heterogeneidade na expressão desses marcadores, característica intrínseca dos gliomas, e salientaram a necessidade de estudos focados em populações puras.

Ao caracterizar a expressão gênica da micróglia humana proveniente de amostras de autópsia, pudemos verificar que esta apresenta genes que a classificam como uma célula altamente especializada às suas funções de célula apresentadora de antígenos, de fagócito, mas principalmente de neuroproteção e manutenção da homeostase cerebral. Essas últimas características são as mais afetadas ao longo do envelhecimento. A comparação dos nossos dados da micróglia humana com dados sobre a micróglia de camundongos disponíveis na literatura evidenciou grandes diferenças estre as espécies, principalmente relacionado às mudanças que ocorrem durante o envelhecimento. Pudemos concluir, também, que há pouca diferença entre homens e mulheres no que diz respeito à expressão gênica da micróglia, ainda que estudos adicionais com um maior número de amostras femininas se faça necessário.

Nossos dados preliminares de análise da expressão gênica de micróglia isolada de amostras de glioma confirmou que os marcadores específicos de micróglia identificados em nosso estudo permanecem estáveis em condições patológicas. Os marcadores encontrados para macrófagos encontram-se pouco expressos nessa micróglia tumoral, indicando o potencial desses marcadores ara análises futuras.

7. REFERÊNCIAS

1. Ostrom QT, Gittleman H, Fulop J, Liu M, Blanda R, Kromer C, et al. CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2008-2012. Neuro-Oncol. outubro de 2015;17 Suppl 4:iv1-iv62.

2. Collins VP. Brain tumours: classification and genes. J Neurol Neurosurg Psychiatry. junho de 2004;75 Suppl 2:ii2-11.

3. Chen R, Cohen AL, Colman H. Targeted Therapeutics in Patients With High-Grade Gliomas: Past, Present, and Future. Curr Treat Options Oncol. agosto de 2016;17(8):42.

4. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol (Berl). agosto de 2007;114(2):97–109.

5. Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella- Branger D, Cavenee WK, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol (Berl). junho de 2016;131(6):803–20.

6. Parsons DW, Jones S, Zhang X, Lin JC-H, Leary RJ, Angenendt P, et al. An integrated genomic analysis of human glioblastoma multiforme. Science. 26 de setembro de 2008;321(5897):1807–12.

7. Ichimura K, Ohgaki H, Kleihues P, Collins VP. Molecular pathogenesis of astrocytic tumours. J Neurooncol. novembro de 2004;70(2):137– 60.

8. Reifenberger G, Collins VP. Pathology and molecular genetics of astrocytic gliomas. J Mol Med Berl Ger. outubro de 2004;82(10):656–70.

9. Reis GF, Tihan T. Therapeutic targets in pilocytic astrocytoma based on genetic analysis. Semin Pediatr Neurol. março de 2015;22(1):23–7.

10. Frequent gains at chromosome 7q34 involving BRAF in pilocytic astrocytoma. - PubMed - NCBI [Internet]. [citado 4 de agosto de 2016]. Available at:

http://www.ncbi.nlm.nih.gov/pubmed/?term=Frequent+gains+at+chromosome+7 q34+involving+BRAF+in+pilocytic+astrocytoma

11. Deshmukh H, Yeh TH, Yu J, Sharma MK, Perry A, Leonard JR, et al. High-resolution, dual-platform aCGH analysis reveals frequent HIPK2 amplification and increased expression in pilocytic astrocytomas. Oncogene. 7 de agosto de 2008;27(34):4745–51.

12. Pfister S, Janzarik WG, Remke M, Ernst A, Werft W, Becker N, et al. BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas. J Clin Invest. maio de 2008;118(5):1739–49.

13. Kamoun A, Idbaih A, Dehais C, Elarouci N, Carpentier C, Letouzé E, et al. Integrated multi-omics analysis of oligodendroglial tumours identifies three subgroups of 1p/19q co-deleted gliomas. Nat Commun. 19 de abril de 2016;7:11263.

14. Foote MB, Papadopoulos N, Diaz LA. Genetic Classification of Gliomas: Refining Histopathology. Cancer Cell. 13 de julho de 2015;28(1):9–11. 15. Ichimura K, Narita Y, Hawkins CE. Diffusely infiltrating astrocytomas: pathology, molecular mechanisms and markers. Acta Neuropathol (Berl). junho de 2015;129(6):789–808.

16. Furnari FB, Fenton T, Bachoo RM, Mukasa A, Stommel JM, Stegh A, et al. Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev. 1 de novembro de 2007;21(21):2683–710.

17. Binder DC, Davis AA, Wainwright DA. Immunotherapy for cancer in the central nervous system: Current and future directions. Oncoimmunology. fevereiro de 2016;5(2):e1082027.

18. Cancer Genome Atlas Research Network, Brat DJ, Verhaak RGW, Aldape KD, Yung WKA, Salama SR, et al. Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas. N Engl J Med. 25 de junho de 2015;372(26):2481–98.

19. Ceccarelli M, Barthel FP, Malta TM, Sabedot TS, Salama SR, Murray BA, et al. Molecular Profiling Reveals Biologically Discrete Subsets and Pathways of Progression in Diffuse Glioma. Cell. 28 de janeiro de 2016;164(3):550–63.

20. Wesseling P, van den Bent M, Perry A. Oligodendroglioma: pathology, molecular mechanisms and markers. Acta Neuropathol (Berl). junho de 2015;129(6):809–27.

21. Cloughesy TF, Cavenee WK, Mischel PS. Glioblastoma: from molecular pathology to targeted treatment. Annu Rev Pathol. 2014;9:1–25.

22. Ohgaki H, Kleihues P. The definition of primary and secondary glioblastoma. Clin Cancer Res Off J Am Assoc Cancer Res. 15 de fevereiro de 2013;19(4):764–72.

23. Verhaak RGW, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 19 de janeiro de 2010;17(1):98–110.

24. Stieber D, Golebiewska A, Evers L, Lenkiewicz E, Brons NHC, Nicot N, et al. Glioblastomas are composed of genetically divergent clones with distinct tumourigenic potential and variable stem cell-associated phenotypes. Acta Neuropathol (Berl). fevereiro de 2014;127(2):203–19.

25. Phillips HS, Kharbanda S, Chen R, Forrest WF, Soriano RH, Wu TD, et al. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell. março de 2006;9(3):157–73.

26. Brennan CW, Verhaak RGW, McKenna A, Campos B, Noushmehr H, Salama SR, et al. The somatic genomic landscape of glioblastoma. Cell. 10 de outubro de 2013;155(2):462–77.

27. Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 19 de fevereiro de 2009;360(8):765–73.

28. Rogozin IB, Pavlov YI. Theoretical analysis of mutation hotspots and their DNA sequence context specificity. Mutat Res. setembro de 2003;544(1):65–85.

29. Filbin MG, Suvà ML. Gliomas Genomics and Epigenomics: Arriving at the Start and Knowing It for the First Time. Annu Rev Pathol. 23 de maio de 2016;11:497–521.

30. Charles NA, Holland EC, Gilbertson R, Glass R, Kettenmann H. The brain tumor microenvironment. Glia. agosto de 2011;59(8):1169–80.

31. Hambardzumyan D, Bergers G. Glioblastoma: Defining Tumor Niches. Trends Cancer. dezembro de 2015;1(4):252–65.

32. Hambardzumyan D, Gutmann DH, Kettenmann H. The role of microglia and macrophages in glioma maintenance and progression. Nat Neurosci. 29 de dezembro de 2015;19(1):20–7.

33. Ransohoff RM, El Khoury J. Microglia in Health and Disease. Cold Spring Harb Perspect Biol. janeiro de 2016;8(1):a020560.

34. Tremblay M-È, Lecours C, Samson L, Sánchez-Zafra V, Sierra A. From the Cajal alumni Achúcarro and Río-Hortega to the rediscovery of never- resting microglia. Front Neuroanat. 2015;9:45.

35. 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. junho de 2005;8(6):752–8.

36. Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science. 27 de maio de 2005;308(5726):1314–8.

37. 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. 5 de novembro de 2010;330(6005):841–5.

38. Hoeffel G, Chen J, Lavin Y, Low D, Almeida FF, See P, et al. C- Myb(+) erythro-myeloid progenitor-derived fetal monocytes give rise to adult tissue-resident macrophages. Immunity. 21 de abril de 2015;42(4):665–78.

39. Schulz C, Gomez Perdiguero E, Chorro L, Szabo-Rogers H, Cagnard N, Kierdorf K, et al. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science. 6 de abril de 2012;336(6077):86–90.

40. Kierdorf K, Erny D, Goldmann T, Sander V, Schulz C, Perdiguero EG, et al. Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8- dependent pathways. Nat Neurosci. 20 de janeiro de 2013;16(3):273–80.

41. Ginhoux F, Prinz M. Origin of microglia: current concepts and past controversies. Cold Spring Harb Perspect Biol. agosto de 2015;7(8):a020537.

42. Ginhoux F, Guilliams M. Tissue-Resident Macrophage Ontogeny and Homeostasis. Immunity. 15 de março de 2016;44(3):439–49.

43. Ransohoff RM. Microglia and monocytes: ’tis plain the twain meet in the brain. Nat Neurosci. setembro de 2011;14(9):1098–100.

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

45. Elmore MRP, Najafi AR, Koike MA, Dagher NN, Spangenberg EE, Rice RA, et al. Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron. 16 de abril de 2014;82(2):380–97.

46. Bruttger J, Karram K, Wörtge S, Regen T, Marini F, Hoppmann N, et al. Genetic Cell Ablation Reveals Clusters of Local Self-Renewing Microglia in the Mammalian Central Nervous System. Immunity. 21 de julho de 2015;43(1):92–106.

47. Shemer A, Erny D, Jung S, Prinz M. Microglia Plasticity During Health and Disease: An Immunological Perspective. Trends Immunol. outubro de 2015;36(10):614–24.

48. Tremblay M-È, Lowery RL, Majewska AK. Microglial interactions with synapses are modulated by visual experience. PLoS Biol. 2010;8(11):e1000527.

49. Colton CA, Chernyshev ON, Gilbert DL, Vitek MP. Microglial contribution to oxidative stress in Alzheimer’s disease. Ann N Y Acad Sci. 2000;899:292–307.

50. Karperien A, Ahammer H, Jelinek HF. Quantitating the subtleties of microglial morphology with fractal analysis. Front Cell Neurosci. 2013;7:3.

51. Kettenmann H, Hanisch U-K, Noda M, Verkhratsky A. Physiology of microglia. Physiol Rev. abril de 2011;91(2):461–553.

52. Paolicelli RC, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P, et al. Synaptic pruning by microglia is necessary for normal brain development. Science. 9 de setembro de 2011;333(6048):1456–8.

53. 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. 24 de maio de 2012;74(4):691–705.

54. Parkhurst CN, Yang G, Ninan I, Savas JN, Yates JR, Lafaille JJ, et al. Microglia promote learning-dependent synapse formation through brain- derived neurotrophic factor. Cell. 19 de dezembro de 2013;155(7):1596–609.

55. Ueno M, Fujita Y, Tanaka T, Nakamura Y, Kikuta J, Ishii M, et al. Layer V cortical neurons require microglial support for survival during postnatal development. Nat Neurosci. maio de 2013;16(5):543–51.

56. Wu Y, Dissing-Olesen L, MacVicar BA, Stevens B. Microglia: Dynamic Mediators of Synapse Development and Plasticity. Trends Immunol. outubro de 2015;36(10):605–13.

57. Brown GC, Neher JJ. Microglial phagocytosis of live neurons. Nat Rev Neurosci. abril de 2014;15(4):209–16.

58. Sokolowski JD, Chabanon-Hicks CN, Han CZ, Heffron DS, Mandell JW. Fractalkine is a “find-me” signal released by neurons undergoing ethanol- induced apoptosis. Front Cell Neurosci. 2014;8:360.

59. Hanisch U-K, Kettenmann H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci. novembro de 2007;10(11):1387–94.

60. Heppner FL, Ransohoff RM, Becher B. Immune attack: the role of inflammation in Alzheimer disease. Nat Rev Neurosci. junho de 2015;16(6):358– 72.

61. Sanchez-Guajardo V, Tentillier N, Romero-Ramos M. The relation between α-synuclein and microglia in Parkinson’s disease: Recent developments. Neuroscience. 27 de agosto de 2015;302:47–58.

62. Mahad DH, Trapp BD, Lassmann H. Pathological mechanisms in progressive multiple sclerosis. Lancet Neurol. fevereiro de 2015;14(2):183–93.

63. Ajami B, Bennett JL, Krieger C, McNagny KM, Rossi FMV. Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nat Neurosci. setembro de 2011;14(9):1142–9.

64. Vainchtein ID, Vinet J, Brouwer N, Brendecke S, Biagini G, Biber K, et al. In acute experimental autoimmune encephalomyelitis, infiltrating macrophages are immune activated, whereas microglia remain immune suppressed. Glia. outubro de 2014;62(10):1724–35.

65. Shi C, Pamer EG. Monocyte recruitment during infection and inflammation. Nat Rev Immunol. novembro de 2011;11(11):762–74.

66. Hickey WF, Kimura H. Perivascular microglial cells of the CNS are bone marrow-derived and present antigen in vivo. Science. 15 de janeiro de 1988;239(4837):290–2.

67. Flügel A, Bradl M, Kreutzberg GW, Graeber MB. Transformation of donor-derived bone marrow precursors into host microglia during autoimmune CNS inflammation and during the retrograde response to axotomy. J Neurosci Res. 1 de outubro de 2001;66(1):74–82.

68. Massengale M, Wagers AJ, Vogel H, Weissman IL. Hematopoietic cells maintain hematopoietic fates upon entering the brain. J Exp Med. 16 de maio de 2005;201(10):1579–89.

69. Hao N-B, Lü M-H, Fan Y-H, Cao Y-L, Zhang Z-R, Yang S-M. Macrophages in tumor microenvironments and the progression of tumors. Clin Dev Immunol. 2012;2012:948098.

70. Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. novembro de 2002;23(11):549–55.

71. Galdiero MR, Garlanda C, Jaillon S, Marone G, Mantovani A. Tumor associated macrophages and neutrophils in tumor progression. J Cell Physiol. julho de 2013;228(7):1404–12.

72. Ellert-Miklaszewska A, Dabrowski M, Lipko M, Sliwa M, Maleszewska M, Kaminska B. Molecular definition of the pro-tumorigenic phenotype of glioma-activated microglia. Glia. 1 de julho de 2013;61(7):1178–90.

73. Gabrusiewicz K, Hossain MB, Cortes-Santiago N, Fan X, Kaminska B, Marini FC, et al. Macrophage Ablation Reduces M2-Like Populations and Jeopardizes Tumor Growth in a MAFIA-Based Glioma Model. Neoplasia N Y N. abril de 2015;17(4):374–84.

74. Ghoochani A, Schwarz MA, Yakubov E, Engelhorn T, Doerfler A, Buchfelder M, et al. MIF-CD74 signaling impedes microglial M1 polarization and facilitates brain tumorigenesis. Oncogene. 9 de maio de 2016;

75. Nakagawa Y, Chiba K. Role of microglial m1/m2 polarization in relapse and remission of psychiatric disorders and diseases. Pharm Basel Switz. 2014;7(12):1028–48.

76. Solinas G, Germano G, Mantovani A, Allavena P. Tumor- associated macrophages (TAM) as major players of the cancer-related inflammation. J Leukoc Biol. novembro de 2009;86(5):1065–73.

77. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 24 de julho de 2008;454(7203):436–44.

78. Pollard JW. Trophic macrophages in development and disease. Nat Rev Immunol. abril de 2009;9(4):259–70.

79. Glass R, Synowitz M. CNS macrophages and peripheral myeloid cells in brain tumours. Acta Neuropathol (Berl). setembro de 2014;128(3):347– 62.

80. Muramatsu M, Yamamoto S, Osawa T, Shibuya M. Vascular endothelial growth factor receptor-1 signaling promotes mobilization of macrophage lineage cells from bone marrow and stimulates solid tumor growth. Cancer Res. 15 de outubro de 2010;70(20):8211–21.

81. Brandenburg S, Müller A, Turkowski K, Radev YT, Rot S, Schmidt C, et al. Resident microglia rather than peripheral macrophages promote vascularization in brain tumors and are source of alternative pro-angiogenic factors. Acta Neuropathol (Berl). março de 2016;131(3):365–78.

82. Bettinger I, Thanos S, Paulus W. Microglia promote glioma migration. Acta Neuropathol (Berl). abril de 2002;103(4):351–5.

83. Ye X, Xu S, Xin Y, Yu S, Ping Y, Chen L, et al. Tumor-associated microglia/macrophages enhance the invasion of glioma stem-like cells via TGF-

1 signaling pathway. J Immunol Baltim Md 1950. 1 de julho de 2012;189(1):444– 53.

84. Sarkar S, Döring A, Zemp FJ, Silva C, Lun X, Wang X, et al. Therapeutic activation of macrophages and microglia to suppress brain tumor- initiating cells. Nat Neurosci. janeiro de 2014;17(1):46–55.

85. Zhou W, Ke SQ, Huang Z, Flavahan W, Fang X, Paul J, et al. Periostin secreted by glioblastoma stem cells recruits M2 tumour-associated

macrophages and promotes malignant growth. Nat Cell Biol. 12 de janeiro de 2015;

86. Szatmári T, Lumniczky K, Désaknai S, Trajcevski S, Hídvégi EJ, Hamada H, et al. Detailed characterization of the mouse glioma 261 tumor model for experimental glioblastoma therapy. Cancer Sci. junho de 2006;97(6):546–53.

87. Steed TC, Treiber JM, Patel K, Ramakrishnan V, Merk A, Smith AR, et al. Differential localization of glioblastoma subtype: implications on glioblastoma pathogenesis. Oncotarget. 1 de abril de 2016;

88. Li R, Li H, Yan W, Yang P, Bao Z, Zhang C, et al. Genetic and clinical characteristics of primary and secondary glioblastoma is associated with differential molecular subtype distribution. Oncotarget. 30 de março de 2015;6(9):7318–24.

89. Natesh K, Bhosale D, Desai A, Chandrika G, Pujari R, Jagtap J, et al. Oncostatin-M differentially regulates mesenchymal and Proneural signature genes in gliomas via STAT3 signaling. Neoplasia N Y N. fevereiro de 2015;17(2):225–37.

90. Devinsky O, Vezzani A, Najjar S, Lanerolle NCD, Rogawski MA. Glia and epilepsy: excitability and inflammation. Trends Neurosci. 1 de março de 2013;36(3):174–84.

91. Eyo UB, Murugan M, Wu L-J. Microglia-Neuron Communication in Epilepsy. Glia. 18 de maio de 2016;

92. Grinberg LT, Ferretti RE de L, Farfel JM, Leite R, Pasqualucci CA, Rosemberg S, et al. Brain bank of the Brazilian aging brain study group - a milestone reached and more than 1,600 collected brains. Cell Tissue Bank. 2007;8(2):151–62.

93. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology. julho de 1984;γ4(7):9γ9–44.

94. Kent WJ. BLAT--the BLAST-like alignment tool. Genome Res. abril de 2002;12(4):656–64.

95. Valente V, Teixeira SA, Neder L, Okamoto OK, Oba-Shinjo SM, Marie SKN, et al. Selection of suitable housekeeping genes for expression analysis in glioblastoma using quantitative RT-PCR. BMC Mol Biol. 2009;10:17. 96. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods San Diego Calif. dezembro de 2001;25(4):402–8.

97. Kim D, Pertea G, Trapnell C, Pimentel H, Kelley R, Salzberg SL. TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol. 25 de abril de 2013;14(4):R36.

98. Anders S, Pyl PT, Huber W. HTSeq - A Python framework to work with high-throughput sequencing data. Bioinforma Oxf Engl. 25 de setembro de 2014;31(2):166–9.

99. DeLuca DS, Levin JZ, Sivachenko A, Fennell T, Nazaire M-D, Williams C, et al. RNA-SeQC: RNA-seq metrics for quality control and process optimization. Bioinforma Oxf Engl. 1 de junho de 2012;28(11):1530–2.

100. Durinck S, Spellman PT, Birney E, Huber W. Mapping identifiers for the integration of genomic datasets with the R/Bioconductor package biomaRt. Nat Protoc. janeiro de 2009;4(8):1184–91.

101. Robinson MD, McCarthy DJ, Smyth GK. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinforma Oxf Engl. 1 de janeiro de 2010;26(1):139–40.

102. Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O’Keeffe S, et al. An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex. J Neurosci Off J Soc Neurosci. 3 de setembro de 2014;34(36):11929–47.

103. Butovsky O, Jedrychowski MP, Moore CS, Cialic R, Lanser AJ, Gabriely G, et al. Identification of a unique TGF- -dependent molecular and functional signature in microglia. Nat Neurosci. janeiro de 2014;17(1):131–43.

104. Hickman SE, Kingery ND, Ohsumi TK, Borowsky ML, Wang L, Means TK, et al. The microglial sensome revealed by direct RNA sequencing. Nat Neurosci. dezembro de 2013;16(12):1896–905.

105. Saeed S, Quintin J, Kerstens HHD, Rao NA, Aghajanirefah A, Matarese F, et al. Epigenetic programming of monocyte-to-macrophage

differentiation and trained innate immunity. Science. 25 de setembro de 2014;345(6204):1251086–1251086.

106. Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinforma Oxf Engl. 1 de janeiro de 2013;29(1):15–21.

107. Li B, Dewey CN. RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinformatics. janeiro de 2011;12:323.

108. Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. 2015;43(7).

109. Olah M, Amor S, Brouwer N, Vinet J, Eggen B, Biber K, et al. Identification of a microglia phenotype supportive of remyelination. Glia. fevereiro de 2012;60(2):306–21.

110. Mistry M, Gillis J, Pavlidis P. Meta-analysis of gene coexpression networks in the post-mortem prefrontal cortex of patients with schizophrenia and unaffected controls. BMC Neurosci. janeiro de 2013;14:105.

111. Zhang B, Gaiteri C, Bodea L-G, Wang Z, McElwee J, Podtelezhnikov AA, et al. Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer’s disease. Cell. β5 de abril de 2013;153(3):707–20.

112. Chen Y, Won SJ, Xu Y, Swanson RA. Targeting microglial activation in stroke therapy: pharmacological tools and gender effects. Curr Med Chem. janeiro de 2014;21(19):2146–55.

113. Lenz KM, McCarthy MM. A starring role for microglia in brain sex differences. Neurosci Rev J Bringing Neurobiol Neurol Psychiatry. junho de 2015;21(3):306–21.

114. Ma W, Cojocaru R, Gotoh N, Gieser L, Villasmil R, Cogliati T, et al. Gene expression changes in aging retinal microglia: relationship to microglial support functions and regulation of activation. Neurobiol Aging. outubro de 2013;34(10):2310–21.

115. Raj DDA, Jaarsma D, Holtman IR, Olah M, Ferreira FM, Schaafsma W, et al. Priming of microglia in a DNA-repair deficient model of accelerated aging. Neurobiol Aging. 9 de setembro de 2014;35(9):2147–60.

116. Holtman IR, Raj DD, Miller JA, Schaafsma W, Yin Z, Brouwer N, et al. Induction of a common microglia gene expression signature by aging and neurodegenerative conditions: a co-expression meta-analysis. Acta Neuropathol Commun. janeiro de 2015;3:31.

117. Dendrou CA, Fugger L, Friese MA. Immunopathology of multiple sclerosis. Nat Rev Immunol. 7 de agosto de 2015;15(9):545–58.

118. Mizutani M, Pino PA, Saederup N, Charo IF, Ransohoff RM, Cardona AE. The fractalkine receptor but not CCR2 is present on microglia from embryonic development throughout adulthood. J Immunol Baltim Md 1950. 1 de janeiro de 2012;188(1):29–36.

119. van der Valk P, De Groot CJ. Staging of multiple sclerosis (MS) lesions: pathology of the time frame of MS. Neuropathol Appl Neurobiol. fevereiro de 2000;26(1):2–10.

120. Komohara Y, Niino D, Saito Y, Ohnishi K, Horlad H, Ohshima K, et al. Clinical significance of CD163+ tumor-associated macrophages in patients

with adult T-cell leukemia/lymphoma. Cancer Sci. julho de 2013;104(7):945–51. 121. Hagerling C, Casbon A-J, Werb Z. Balancing the innate immune system in tumor development. Trends Cell Biol. abril de 2015;25(4):214–20.

122. Prosniak M, Harshyne LA, Andrews DW, Kenyon LC, Bedelbaeva K, Apanasovich TV, et al. Glioma grade is associated with the accumulation and