Neuroprotection mediated through estrogen receptor-alpha in astrocytes - PubMed (original) (raw)

. 2011 May 24;108(21):8867-72.

doi: 10.1073/pnas.1103833108. Epub 2011 May 9.

Mary E Hamby, Elizabeth Umeda, Noriko Itoh, Sienmi Du, Amy J Wisdom, Yuan Cao, Galyna Bondar, Jeannie Lam, Yan Ao, Francisco Sandoval, Silvie Suriany, Michael V Sofroniew, Rhonda R Voskuhl

Affiliations

Neuroprotection mediated through estrogen receptor-alpha in astrocytes

Rory D Spence et al. Proc Natl Acad Sci U S A. 2011.

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.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Fig. 1.

(A and B) Verification of gene deletion specificity in astrocyte-ERα-CKO (aCKO) and neuronal-ERα-CKO (nCKO) mouse models. (C and D) EAE clinical disease severity scores showing that protective effects of ERα ligand require ERα in astrocytes, but not neurons. (A) Immunohistochemistry shows ERα colocalized with NeuN and DAPI in WT and aCKO mice with EAE, but not in nCKO mice with EAE. (B) ERα is colocalized with GFAP and DAPI in WT and nCKO mice with EAE, but not in aCKO mice with EAE. (Scale bars, 15 μm.) (C) WT and nCKO mice with EAE and given ERα ligand both had significantly better clinical scores compared with WT and nCKO mice with EAE and given vehicle. n = 6 per group. (D) Only WT mice, but not aCKO mice, with EAE and given ERα ligand had significantly better clinical scores compared with WT or aCKO mice with EAE and given vehicle. n = 12 per group. *P < 0.05 (repeated-measures ANOVA with post hoc Bonferroni pairwise analysis).

Fig. 2.

Fig. 2.

Immunohistochemical evidence that ERα is required in astrocytes, but not neurons, to reduce numbers of Iba-1 globoid macrophages and CD3 T cells in dorsal column white matter. (A) Iba-1 globoid macrophages were significantly reduced in WT and nCKO mice with EAE treated with ERα ligand, but not in aCKO mice with EAE treated with ERα ligand. (B) Iba-1 ramified microglia exhibited no significant difference in number across all experimental groups. (C) CD3 T cells were reduced in WT and nCKO mice with EAE treated with ERα ligand, but not in aCKO mice with EAE treated with ERα ligand. (Scale bar, 15 μm.) n = 6 per group. *P < 0.05; NS, not significant vs. WT+No EAE; #P < 0.05 vs. WT+EAE+Veh, aCKO+EAE+Veh, or aCKO+EAE+ERα ligand (ANOVA with post hoc Bonferroni pairwise analysis).

Fig. 3.

Fig. 3.

Flow cytometry evidence that ERα is required in astrocytes, but not neurons, to reduce macrophage and T-cell inflammation. (A and C) Macrophages (R1) (CD11bhi/CD45hi) and (B and C) T-cells (CD45hi/CD3hi) were significantly reduced in WT, but not aCKO mice, treated with ERα ligand via flow cytometry from the CNS. (A and C) There were no significant differences among all groups in numbers of microglia (R2) (CD11bhi/CD45int). n = 5 per group. *P < 0.05. NS, not significant vs. WT+EAE+ERα ligand (ANOVA with post hoc Bonferroni pairwise analysis).

Fig. 4.

Fig. 4.

Immunohistochemical evidence that ERα is required in astrocytes, but not neurons, to protect against axonal loss and reactive astrogliosis. (A) MBP stained intensity and area were significantly reduced in all EAE groups, but were not significantly altered by ERα ligand treatment in any group. (Scale bar, 120 μm.) (B) Numbers of NF200+ axons were significantly reduced in WT mice with EAE; and treatment with ERα ligand ameliorated axonal loss in WT and nCKO mice, but not aCKO mice, with EAE. (Scale bar, 20 μm.) (C) GFAP stained area was significantly increased in WT mice with EAE; and treatment with ERα ligand ameliorated this increase in WT and nCKO mice, but not aCKO mice, with EAE. (Scale bar, 40 μm.) n = 6 per group. *P < 0.05; NS, not significant vs. WT+No EAE (ANOVA with post hoc Bonferroni pairwise analysis).

Similar articles

Cited by

References

    1. Brinton RD. Estrogen regulation of glucose metabolism and mitochondrial function: therapeutic implications for prevention of Alzheimer's disease. Adv Drug Deliv Rev. 2008;60:1504–1511. - PMC - PubMed
    1. Lee SJ, McEwen BS. Neurotrophic and neuroprotective actions of estrogens and their therapeutic implications. Annu Rev Pharmacol Toxicol. 2001;41:569–591. - PubMed
    1. Wise PM. Estrogens and neuroprotection. Trends Endocrinol Metab. 2002;13:229–230. - PubMed
    1. Kim S, Liva SM, Dalal MA, Verity MA, Voskuhl RR. Estriol ameliorates autoimmune demyelinating disease: Implications for multiple sclerosis. Neurology. 1999;52:1230–1238. - PubMed
    1. Trapp BD, Nave K-A. Multiple sclerosis: An immune or neurodegenerative disorder? Annu Rev Neurosci. 2008;31:247–269. - PubMed

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources