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Role of estrogen receptors in the regulation of reactive gliosis

Luis M. Garcia-Segura1*, Maria Angeles Arevalo1, Inigo Azcoitia2 and George E. Barreto3
  • 1 Consejo Superior de Investigaciones Científicas, Instituto Cajal, Spain
  • 2 Universidad Complutense de Madrid, Biologia Celular, Spain
  • 3 Pontificia Universidad Javeriana, Department of Nutrition and Biochemistry, Colombia

Although estradiol may directly act on neurons to promote neuroprotection in vitro, the participation of other cell types is also necessary to maintain global tissue homeostasis in vivo (Arevalo et al., 2010; Johann and Beyer, 2013; Acaz-Fonseca et al., 2014). Thus, estradiol acts on glial and endothelial cells to maintain the function of the neurovascular unit, regulates gliosis and the inflammatory response of astrocytes and microglia to control neuroinflammation and acts on neurons, astrocytes and oligodendrocytes to maintain the function and propagating properties of neuronal circuits (Garcia-Ovejero et al., 2005; Tapia-Gonzalez et al., 2008; Barrerto et al., 2009; Cerciat et al., 2010; López Rodríguez et al., 2011; Barreto et al., 2014). Glial cells express estrogen receptors (ERs), including ERalpha, ERbeta and G protein-coupled estrogen receptor-1 (GPER) (Garcia-Ovjero et al., 2005; Dhandapani and Brann, 2007) and brain injury induces both the synthesis of estradiol in both reactive astrocytes and the expression of ERs in these cells (Garcia-Ovejero et al., 2002). This suggests that astrocytes may play an important role in the neuroprotective actions of estradiol. Indeed, recent studies, using conditional KO mice for ERalpha and ERbeta, have shown that in an experimental model of multiple sclerosis the protective action of estradiol is mediated by ERalpha expressed in astrocytes, but not by ERalpha expressed in neurons or ERbeta expressed in astrocytes or neurons (Spence et al., 2013). ERs in glial cells activate several neuroprotective mechanisms in response to estradiol, including the release of factors that have trophic effects on neurons and other cell types and the control of neuroinflammation, edema and extracellular glutamate levels. Classical ERs associated with the plasma membrane of astrocytes are involved in the estradiol-induced release of transforming growth factor (TGF)-beta, through the activation of the PI3K/Akt signaling pathway (Sortino et al., 2004; Dhandapani et al., 2005). In addition, both ERalpha and ERbeta are involved in the anti-inflammatory and anti-gliotic actions of estradiol on microglia and astrocytes (Vegeto et al., 2003; Liu et al., 2005). The anti-inflammatory action of ERalpha is also exerted through the activation of the PI3K pathway, which in turns blocks nuclear factor kB (NFkB) activation and translocation to the cell nucleus (Ghisletti et al., 2005). ERbeta also plays an essential role in the regulation of the neuroinflammatory response of astrocytes. This effect is in part mediated by the upregulation of neuroglobin (De Marinis et al., 2013), a hemoprotein with partial sequence identity with vertebrate hemoglobin and myoglobin, which protects neurons from a variety of insults, such as hypoxia, glucose deprivation, oxidative stress, beta-amyloid toxicity and experimental stroke.

References

Acaz-Fonseca, E., Sanchez-Gonzalez, R., Azcoitia, I., Arevalo, M.A., and Garcia-Segura, L.M. (2014). Role of astrocytes in the neuroprotective actions of 17beta-estradiol and selective estrogen receptor modulators. Mol. Cell. Endocrinol. 389, 48-57.

Arevalo, M.A., Santos-Galindo, M., Bellini, M.J., Azcoitia, I., and Garcia-Segura, L.M. (2010). Actions of estrogens on glial cells: Implications for neuroprotection. Biochim. Biophys. Acta 1800, 1106-1112.

Barreto, G., Santos-Galindo, M., Diz-Chaves, Y., Pernía, O., Carrero, P., Azcoitia, I., et al. (2009). Selective estrogen receptor modulators decrease reactive astrogliosis in the injured brain: effects of aging and prolonged depletion of ovarian hormones. Endocrinology 150, 5010-5015.

Barreto, G.E., Santos-Galindo, M., and Garcia-Segura, L.M. (2014). Selective estrogen receptor modulators regulate reactive microglia after penetrating brain injury. Front. Aging Neurosci. 6, 132.

Cerciat, M., Unkila, M., Garcia-Segura, L.M., and Arevalo, M.A. (2010). Selective estrogen receptor modulators decrease the production of interleukin-6 and interferon-gamma-inducible protein-10 by astrocytes exposed to inflammatory challenge in vitro. Glia 58, 93-102.

De Marinis, E. Acaz-Fonseca, E., Arevalo, M.A., Ascenzi, P., Fiocchetti, M., Marino, M., et al. (2013). 17beta-Oestradiol anti-inflammatory effects in primary astrocytes require oestrogen receptor beta-mediated neuroglobin up-regulation. J. Neuroendocrinol. 25, 260-270.

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Dhandapani, K.M., Wade, F.M., Mahesh, V.B., and Brann, D.W. (2005). Astrocyte-derived transforming growth factor-{beta} mediates the neuroprotective effects of 17{beta}-estradiol: involvement of nonclassical genomic signaling pathways. Endocrinology 146, 2749-2759.

Garcia-Ovejero, D., Veiga, S., Garcia-Segura, L.M., and Doncarlos, L.L. (2002). Glial expression of estrogen and androgen receptors after rat brain injury. J. Comp. Neurol. 450, 256-271.

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Johann, S., and Beyer, C. (2013). Neuroprotection by gonadal steroid hormones in acute brain damage requires cooperation with astroglia and microglia. J. Steroid Biochem. Mol. Biol. 137, 71-81.

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Spence, R.D., Wisdom, A.J., Cao, Y., Hill, H.M., Mongerson, C.R., Stapornkul, B., et al., (2013). Estrogen mediates neuroprotection and anti-inflammatory effects during EAE through ERalpha signaling on astrocytes but not through ERbeta signaling on astrocytes or neurons. J. Neurosci. 33, 10924-10933.

Tapia-Gonzalez, S., Carrero, P., Pernia, O., Garcia-Segura, L.M., and Diz-Chaves, Y. (2008). Selective oestrogen receptor (ER) modulators reduce microglia reactivity in vivo after peripheral inflammation: potential role of microglial ERs. J. Endocrinol. 198, 219-230.

Vegeto, E. Belcredito, S., Etteri, S., Ghisletti, S., Brusadelli, A., Meda, C., et al. (2003). Estrogen receptor-alpha mediates the brain antiinflammatory activity of estradiol. Proc. Natl. Acad. Sci. U S A 100, 9614-9619.

Liu, X., Fan, X.L., Zhao, Y., Luo, G.R., Li, X.P., Li, R., et al. (2005). Estrogen provides neuroprotection against activated microglia-induced dopaminergic neuronal injury through both estrogen receptor-alpha and estrogen receptor-beta in microglia. J. Neurosci. Res. 81, 653-665.

Keywords: Aromatase, Estradiol, G protein-coupled estrogen receptor-1, Astrocytes, Microglia, nucelar factor kB, Neuroglobin

Conference: Latin-American School on glial cells in the diseased brain (IBRO), Bogotá, Colombia, 13 Jul - 17 Jul, 2015.

Presentation Type: Oral Presentation

Topic: Traumatic and Cerebrovascular diseases

Citation: Garcia-Segura LM, Arevalo M, Azcoitia I and Barreto G (2015). Role of estrogen receptors in the regulation of reactive gliosis. Conference Abstract: Latin-American School on glial cells in the diseased brain (IBRO). doi: 10.3389/conf.fncel.2015.35.00001

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Received: 23 Feb 2015; Published Online: 16 May 2015.

* Correspondence: Prof. Luis M Garcia-Segura, Consejo Superior de Investigaciones Científicas, Instituto Cajal, Madrid, E-28002, Spain, lmgs@cajal.csic.es