title: Neuroprotection mediated through estrogen receptor-alpha in astrocytes.
abstract: 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-α (ERα) 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 ERα ligand-mediated neuroprotective effects in a well-characterized model of adoptive experimental autoimmune encephalomyelitis (EAE). We found that the pronounced and significant neuroprotective effects of systemic treatment with ERα ligand on clinical function, CNS inflammation, and axonal loss during EAE were completely prevented by conditional deletion of ERα from astrocytes, whereas conditional deletion of ERα from neurons had no significant effect. These findings show that signaling through ERα in astrocytes, but not through ERα in neurons, is essential for the beneficial effects of ERα 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.
authors.affiliation: Department of Neurology, University of California Multiple Sclerosis Program, Los Angeles, CA 90095, USA.
authors.forename: Rory D
authors.initials: RD
authors.lastname: Spence
authors.forename: Mary E
authors.initials: ME
authors.lastname: Hamby
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Umeda
authors.forename: Noriko
authors.initials: N
authors.lastname: Itoh
authors.forename: Sienmi
authors.initials: S
authors.lastname: Du
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Wisdom
authors.forename: Yuan
authors.initials: Y
authors.lastname: Cao
authors.forename: Galyna
authors.initials: G
authors.lastname: Bondar
authors.forename: Jeannie
authors.initials: J
authors.lastname: Lam
authors.forename: Yan
authors.initials: Y
authors.lastname: Ao
authors.forename: Francisco
authors.initials: F
authors.lastname: Sandoval
authors.forename: Silvie
authors.initials: S
authors.lastname: Suriany
authors.forename: Michael V
authors.initials: MV
authors.lastname: Sofroniew
authors.forename: Rhonda R
authors.initials: RR
authors.lastname: Voskuhl
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000473:pathology; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000473:pathology*; D047628:Estrogen Receptor alpha / Q000172:deficiency / Q000502:physiology*; D007249:Inflammation / Q000517:prevention & control; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D019636:Neurodegenerative Diseases / Q000517:prevention & control; D009474:Neurons / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*
chemical_list: D047628:Estrogen Receptor alpha; D008024:Ligands; D018696:Neuroprotective Agents