Neuroprotection mediated through estrogen receptor-α in astrocytes

被引:184
作者
Spence, Rory D. [2 ]
Hamby, Mary E. [1 ]
Umeda, Elizabeth [2 ]
Itoh, Noriko [2 ]
Du, Sienmi [2 ]
Wisdom, Amy J. [2 ]
Cao, Yuan [2 ]
Bondar, Galyna [1 ]
Lam, Jeannie [2 ]
Ao, Yan [1 ]
Sandoval, Francisco [2 ]
Suriany, Silvie [2 ]
Sofroniew, Michael V. [1 ]
Voskuhl, Rhonda R. [2 ]
机构
[1] Univ Calif Los Angeles, Dept Neurobiol, Multiple Sclerosis Program, Los Angeles, CA 90095 USA
[2] Univ Calif Los Angeles, Dept Neurol, Multiple Sclerosis Program, Los Angeles, CA 90095 USA
基金
美国国家卫生研究院;
关键词
multiple sclerosis; astrogliosis; conditional knockout; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; SPINAL-CORD-INJURY; MULTIPLE-SCLEROSIS; THERAPEUTIC IMPLICATIONS; REACTIVE ASTROCYTES; BRAIN INJURY; RAT-BRAIN; ER-BETA; DISEASE; EXPRESSION;
D O I
10.1073/pnas.1103833108
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Estrogen has well-documented neuroprotective effects in a variety of clinical and experimental disorders of the CNS, including autoimmune inflammation, traumatic injury, stroke, and neurodegenerative diseases. The beneficial effects of estrogens in CNS disorders include mitigation of clinical symptoms, as well as attenuation of histopathological signs of neurodegeneration and inflammation. The cellular mechanisms that underlie these CNS effects of estrogens are uncertain, because a number of different cell types express estrogen receptors in the peripheral immune system and the CNS. Here, we investigated the potential roles of two endogenous CNS cell types in estrogen-mediated neuroprotection. We selectively deleted estrogen receptor-a (ERa) from either neurons or astrocytes using well-characterized Cre-loxP systems for conditional gene knockout in mice, and studied the effects of these conditional gene deletions on ERa ligand-mediated neuroprotective effects in a wellcharacterized model of adoptive experimental autoimmune encephalomyelitis (EAE). We found that the pronounced and significant neuroprotective effects of systemic treatment with ERa ligand on clinical function, CNS inflammation, and axonal loss during EAE were completely prevented by conditional deletion of ERa from astrocytes, whereas conditional deletion of ERa from neurons had no significant effect. These findings show that signaling through ERa in astrocytes, but not through ERa in neurons, is essential for the beneficial effects of ERa ligand in EAE. Our findings reveal a unique cellular mechanism for estrogen-mediated CNS neuroprotective effects by signaling through astrocytes, and have implications for understanding the pathophysiology of sex hormone effects in diverse CNS disorders.
引用
收藏
页码:8867 / 8872
页数:6
相关论文
共 50 条
[21]   Unliganded estrogen receptor-β regulation of genes is inhibited by tamoxifen [J].
Levy, Nitzan ;
Paruthiyil, Sreenivasan ;
Zhao, Xiaoyue ;
Vivar, Omar I. ;
Saunier, Elise F. ;
Griffin, Chandi ;
Tagliaferri, Mary ;
Cohen, Isaac ;
Speed, Terence P. ;
Leitman, Dale C. .
MOLECULAR AND CELLULAR ENDOCRINOLOGY, 2010, 315 (1-2) :201-207
[22]   Estrogen receptor-β signaling modulates epithelial barrier function [J].
Looijer-van Langen, Mirjam ;
Hotte, Naomi ;
Dieleman, Levinus A. ;
Albert, Eric ;
Mulder, Chris ;
Madsen, Karen L. .
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY, 2011, 300 (04) :G621-G626
[23]   The Role of Estrogen Receptor-β in Breast Cancer [J].
Murphy, Leigh C. ;
Leygue, Etienne .
SEMINARS IN REPRODUCTIVE MEDICINE, 2012, 30 (01) :5-13
[24]   Estrogen Receptor-β Prevents Cardiac Fibrosis [J].
Pedram, Ali ;
Razandi, Mahnaz ;
O'Mahony, Fiona ;
Lubahn, Dennis ;
Levin, Ellis R. .
MOLECULAR ENDOCRINOLOGY, 2010, 24 (11) :2152-2165
[25]   Reversal of fortune: estrogen receptor-β in endometriosis [J].
Simmen, Rosalia C. M. ;
Kelley, Angela S. .
JOURNAL OF MOLECULAR ENDOCRINOLOGY, 2016, 57 (02) :F23-F27
[26]   Estrogen-like neuroprotection of isopsoralen against spinal cord injury through estrogen receptor ERα [J].
Xiao-ming Li ;
Qi Yang ;
Xu-bo Li ;
Qiang Cheng ;
Kun Zhang ;
Jing Han ;
Jian-ning Zhao ;
Gang Liu ;
Ming-gao Zhao .
Metabolic Brain Disease, 2017, 32 :259-265
[27]   Estrogen receptor- ligand treatment after disease onset is neuroprotective in the multiple sclerosis model [J].
Wisdom, Amy J. ;
Cao, Yuan ;
Itoh, Noriko ;
Spence, Rory D. ;
Voskuhl, Rhonda R. .
JOURNAL OF NEUROSCIENCE RESEARCH, 2013, 91 (07) :901-908
[28]   Resveratrol induced neuroprotection is mediated via both estrogen receptor subtypes, ERα, and ERβ [J].
Saleh, Monique C. ;
Connell, Barry J. ;
Saleh, Tarek M. .
NEUROSCIENCE LETTERS, 2013, 548 :217-221
[29]   Astrocytes as a target for neuroprotection: Modulation by progesterone and dehydroepiandrosterone [J].
Arbo, Bruno Dutra ;
Benetti, Fernando ;
Ribeiro, Maria Flavia .
PROGRESS IN NEUROBIOLOGY, 2016, 144 :27-47
[30]   Chronic Exposure to Anabolic Androgenic Steroids Alters Neuronal Function in the Mammalian Forebrain via Androgen Receptor- and Estrogen Receptor- Mediated Mechanisms [J].
Penatti, Carlos A. A. ;
Porter, Donna M. ;
Henderson, Leslie P. .
JOURNAL OF NEUROSCIENCE, 2009, 29 (40) :12484-12496