title: Estradiol inhibits ongoing autoimmune neuroinflammation and NFkappaB-dependent CCL2 expression in reactive astrocytes.
abstract: Astroglial reactivity associated with increased production of NFkappaB-dependent proinflammatory molecules is an important component of the pathophysiology of chronic neurological disorders such as multiple sclerosis (MS). The use of estrogens as potential anti-inflammatory and neuroprotective drugs is a matter of debate. Using mouse experimental allergic encephalomyelitis (EAE) as a model of chronic neuroinflammation, we report that implants reproducing pregnancy levels of 17beta-estradiol (E2) alleviate ongoing disease and decrease astrocytic production of CCL2, a proinflammatory chemokine that drives the local recruitment of inflammatory myeloid cells. Immunohistochemistry and confocal imaging reveal that, in spinal cord white matter EAE lesions, reactive astrocytes express estrogen receptor (ER)alpha (and to a lesser extent ERbeta) with a preferential nuclear localization, whereas other cells including infiltrated leukocytes express ERs only in their membranes or cytosol. In cultured rodent astrocytes, E2 or an ERalpha agonist, but not an ERbeta agonist, inhibits TNFalpha-induced CCL2 expression at nanomolar concentrations, and the ER antagonist ICI 182,170 blocks this effect. We show that this anti-inflammatory action is not associated with inhibition of NFkappaB nuclear translocation but rather involves direct repression of NFkappaB-dependent transcription. Chromatin immunoprecipitation assays further indicate that estrogen suppresses TNFalpha-induced NFkappaB recruitment to the CCL2 enhancer. These data uncover reactive astrocytes as an important target for nuclear ERalpha inhibitory action on chemokine expression and suggest that targeting astrocytic nuclear NFkappaB activation with estrogen receptor alpha modulators may improve therapies of chronic neurodegenerative disorders involving astroglial neuroinflammation.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche en Santé 546, Hôpital Pitié-Salpêtrière, Paris F-75013, France.
authors.forename: Sébastien N
authors.initials: SN
authors.lastname: Giraud
authors.forename: Cécile M
authors.initials: CM
authors.lastname: Caron
authors.forename: Danielle
authors.initials: D
authors.lastname: Pham-Dinh
authors.forename: Patrick
authors.initials: P
authors.lastname: Kitabgi
authors.forename: Arnaud B
authors.initials: AB
authors.lastname: Nicot
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000276:immunology / Q000378:metabolism*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000628:therapy; D004958:Estradiol / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000378:metabolism; D005260:Female; D007962:Leukocytes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D051381:Rats; D013116:Spinal Cord / Q000378:metabolism; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D004958:Estradiol
references.citation: J Immunol. 2009 Mar 1;182(5):3294-303
references.pmid: 19234228
references.citation: J Immunol. 2001 Feb 1;166(3):2080-9
references.pmid: 11160259
references.citation: Neuron. 2008 Nov 6;60(3):430-40
references.pmid: 18995817
references.citation: Brain. 2009 Sep;132(Pt 9):2487-500
references.pmid: 19531531
references.citation: Cell. 2009 Apr 3;137(1):26-8
references.pmid: 19345183
references.citation: Proc Natl Acad Sci U S A. 2007 Apr 3;104(14):6013-8
references.pmid: 17389368
references.citation: Lab Invest. 2009 Oct;89(10):1076-83
references.pmid: 19668239
references.citation: Am J Pathol. 1999 Jan;154(1):45-51
references.pmid: 9916917
references.citation: Am J Pathol. 2004 Dec;165(6):2069-77
references.pmid: 15579449
references.citation: J Immunol. 2003 Dec 1;171(11):6267-74
references.pmid: 14634144
references.citation: J Cell Physiol. 2008 Feb;214(2):456-64
references.pmid: 17654501
references.citation: J Immunol. 2003 Feb 1;170(3):1548-55
references.pmid: 12538720
references.citation: Mol Cell Biol. 2005 Apr;25(8):2957-68
references.pmid: 15798185
references.citation: Proc Natl Acad Sci U S A. 2005 Feb 15;102(7):2543-8
references.pmid: 15699342
references.citation: Proc Natl Acad Sci U S A. 2007 Sep 11;104(37):14813-8
references.pmid: 17785421
references.citation: J Immunol. 2003 Dec 15;171(12):6936-40
references.pmid: 14662901
references.citation: J Neuroinflammation. 2008 Feb 01;5:6
references.pmid: 18237444
references.citation: Oncogene. 2002 May 16;21(22):3603-10
references.pmid: 12032862
references.citation: J Neurol Neurosurg Psychiatry. 2005 Feb;76(2):272-5
references.pmid: 15654051
references.citation: J Neuroimmunol. 2000 Aug 1;108(1-2):192-200
references.pmid: 10900353
references.citation: Exp Gerontol. 2007 Jan-Feb;42(1-2):70-5
references.pmid: 16872778
references.citation: J Neuroimmunol. 2009 Sep 29;214(1-2):67-77
references.pmid: 19664827
references.citation: J Neurosci. 2000 Jan 1;20(1):401-8
references.pmid: 10627616
references.citation: Science. 2001 Nov 23;294(5547):1731-5
references.pmid: 11721059
references.citation: J Endocrinol. 2008 Jul;198(1):219-30
references.pmid: 18460549
references.citation: Am J Pathol. 1999 Nov;155(5):1433-8
references.pmid: 10550297
references.citation: J Comp Neurol. 2001 Apr 23;433(1):115-23
references.pmid: 11283953
references.citation: Cell Tissue Res. 2001 May;304(2):193-214
references.pmid: 11396714
references.citation: Ann Neurol. 2002 Oct;52(4):421-8
references.pmid: 12325070
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 23;101(12):4130-5
references.pmid: 15024130
references.citation: J Exp Med. 2000 Sep 18;192(6):899-905
references.pmid: 10993920
references.citation: J Neurosci. 2002 Dec 15;22(24):10633-42
references.pmid: 12486156
references.citation: J Comp Neurol. 2002 Aug 26;450(3):256-71
references.pmid: 12209854
references.citation: J Immunol. 2009 Mar 1;182(5):2628-40
references.pmid: 19234157
references.citation: J Immunol. 2004 Aug 15;173(4):2435-42
references.pmid: 15294957
references.citation: Blood. 1997 Aug 1;90(3):909-28
references.pmid: 9242519
references.citation: Glia. 2008 Apr 15;56(6):659-74
references.pmid: 18286612
references.citation: Endocr Rev. 1999 Aug;20(4):435-59
references.pmid: 10453354
references.citation: Mol Endocrinol. 2008 Feb;22(2):263-72
references.pmid: 17932106
references.citation: Glia. 2009 May;57(7):777-90
references.pmid: 19031437
references.citation: Neuron. 2003 Jun 5;38(5):685-8
references.pmid: 12797954
references.citation: FASEB J. 1993 Apr 1;7(6):592-600
references.pmid: 8472896
references.citation: Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9614-9
references.pmid: 12878732
references.citation: Nat Chem Biol. 2008 Apr;4(4):241-7
references.pmid: 18344977
references.citation: J Neurosci Res. 2004 Dec 1;78(5):603-24
references.pmid: 15515048
references.citation: Neurology. 1999 Apr 12;52(6):1230-8
references.pmid: 10214749