GPR30 forms an integral part of E2-protective pathway in experimental autoimmune encephalomyelitis

Sheetal Bodhankar, Halina Offner

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

A major focus of our laboratory has been an in-depth evaluation as to how estrogens exert a pronounced protective effect on clinical and histological disease in the animal model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE). An important issue regarding their therapeutic application has been the undesirable estrogenic side effects thought to be mediated primarily through 17β-estradiol (E2) binding to intracellular estrogen receptor alpha (ERα). With the discovery and characterization of GPR30 as the putative membrane estrogen receptor, we sought to study whether signaling through GPR30 was sufficient to mediate protection against EAE without engagement of ERα. Treatment of EAE in WT mice with G-1, a selective GPR30 agonist, retained estradiol's ability to protect against clinical and histological EAE without estrogenic side effects. G-1 treatment deviated cytokine profiles and enhanced suppressive activity of CD4+Foxp3+ Treg cells through a GPR30- and programmed death 1 (PD-1)-dependent mechanism. This novel finding was indicative of the protective effect of GPR30 activation in EAE and provides a strong foundation for the clinical application of GPR30 agonists such as G-1 in MS. However, future studies are needed to elucidate cross-signaling and evaluate possible additive effects of combined signaling through both GPR30 and ER-α. Deciphering the possible mechanism of involvement of GPR30 in estrogenmediated protection against EAE may result in lowering treatment doses of E2 and GPR30 agonists that could minimize risks and maximize immunoregulation and therapeutic effects in MS. Alternatively, one might envision using E2 derivatives with reduced estrogenic activity alone or in combination with GPR30 agonists as therapies for both male and female MS patients.

Original languageEnglish (US)
Pages (from-to)262-274
Number of pages13
JournalImmunology, Endocrine and Metabolic Agents in Medicinal Chemistry
Volume11
Issue number4
StatePublished - Dec 2011

Fingerprint

Autoimmune Experimental Encephalomyelitis
Multiple Sclerosis
Estrogen Receptor alpha
Estrogens
Estradiol
Therapeutics
Animal Disease Models
Therapeutic Uses
Regulatory T-Lymphocytes
Estrogen Receptors
Cytokines
Membranes

Keywords

  • 17β-estradiol
  • Dendritic cells
  • EAE
  • Encephalitogenic t cells
  • ER-α
  • ER-β
  • Estrogen
  • G-1
  • G-15
  • GPR30
  • IL-10
  • IL-17
  • Inflammation
  • MS
  • Tregs

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Immunology and Allergy
  • Pharmacology

Cite this

@article{0111f384ba3c4e85bb790582c543fe67,
title = "GPR30 forms an integral part of E2-protective pathway in experimental autoimmune encephalomyelitis",
abstract = "A major focus of our laboratory has been an in-depth evaluation as to how estrogens exert a pronounced protective effect on clinical and histological disease in the animal model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE). An important issue regarding their therapeutic application has been the undesirable estrogenic side effects thought to be mediated primarily through 17β-estradiol (E2) binding to intracellular estrogen receptor alpha (ERα). With the discovery and characterization of GPR30 as the putative membrane estrogen receptor, we sought to study whether signaling through GPR30 was sufficient to mediate protection against EAE without engagement of ERα. Treatment of EAE in WT mice with G-1, a selective GPR30 agonist, retained estradiol's ability to protect against clinical and histological EAE without estrogenic side effects. G-1 treatment deviated cytokine profiles and enhanced suppressive activity of CD4+Foxp3+ Treg cells through a GPR30- and programmed death 1 (PD-1)-dependent mechanism. This novel finding was indicative of the protective effect of GPR30 activation in EAE and provides a strong foundation for the clinical application of GPR30 agonists such as G-1 in MS. However, future studies are needed to elucidate cross-signaling and evaluate possible additive effects of combined signaling through both GPR30 and ER-α. Deciphering the possible mechanism of involvement of GPR30 in estrogenmediated protection against EAE may result in lowering treatment doses of E2 and GPR30 agonists that could minimize risks and maximize immunoregulation and therapeutic effects in MS. Alternatively, one might envision using E2 derivatives with reduced estrogenic activity alone or in combination with GPR30 agonists as therapies for both male and female MS patients.",
keywords = "17β-estradiol, Dendritic cells, EAE, Encephalitogenic t cells, ER-α, ER-β, Estrogen, G-1, G-15, GPR30, IL-10, IL-17, Inflammation, MS, Tregs",
author = "Sheetal Bodhankar and Halina Offner",
year = "2011",
month = "12",
language = "English (US)",
volume = "11",
pages = "262--274",
journal = "Immunology, Endocrine and Metabolic Agents in Medicinal Chemistry",
issn = "1871-5222",
publisher = "Bentham Science Publishers B.V.",
number = "4",

}

TY - JOUR

T1 - GPR30 forms an integral part of E2-protective pathway in experimental autoimmune encephalomyelitis

AU - Bodhankar, Sheetal

AU - Offner, Halina

PY - 2011/12

Y1 - 2011/12

N2 - A major focus of our laboratory has been an in-depth evaluation as to how estrogens exert a pronounced protective effect on clinical and histological disease in the animal model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE). An important issue regarding their therapeutic application has been the undesirable estrogenic side effects thought to be mediated primarily through 17β-estradiol (E2) binding to intracellular estrogen receptor alpha (ERα). With the discovery and characterization of GPR30 as the putative membrane estrogen receptor, we sought to study whether signaling through GPR30 was sufficient to mediate protection against EAE without engagement of ERα. Treatment of EAE in WT mice with G-1, a selective GPR30 agonist, retained estradiol's ability to protect against clinical and histological EAE without estrogenic side effects. G-1 treatment deviated cytokine profiles and enhanced suppressive activity of CD4+Foxp3+ Treg cells through a GPR30- and programmed death 1 (PD-1)-dependent mechanism. This novel finding was indicative of the protective effect of GPR30 activation in EAE and provides a strong foundation for the clinical application of GPR30 agonists such as G-1 in MS. However, future studies are needed to elucidate cross-signaling and evaluate possible additive effects of combined signaling through both GPR30 and ER-α. Deciphering the possible mechanism of involvement of GPR30 in estrogenmediated protection against EAE may result in lowering treatment doses of E2 and GPR30 agonists that could minimize risks and maximize immunoregulation and therapeutic effects in MS. Alternatively, one might envision using E2 derivatives with reduced estrogenic activity alone or in combination with GPR30 agonists as therapies for both male and female MS patients.

AB - A major focus of our laboratory has been an in-depth evaluation as to how estrogens exert a pronounced protective effect on clinical and histological disease in the animal model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE). An important issue regarding their therapeutic application has been the undesirable estrogenic side effects thought to be mediated primarily through 17β-estradiol (E2) binding to intracellular estrogen receptor alpha (ERα). With the discovery and characterization of GPR30 as the putative membrane estrogen receptor, we sought to study whether signaling through GPR30 was sufficient to mediate protection against EAE without engagement of ERα. Treatment of EAE in WT mice with G-1, a selective GPR30 agonist, retained estradiol's ability to protect against clinical and histological EAE without estrogenic side effects. G-1 treatment deviated cytokine profiles and enhanced suppressive activity of CD4+Foxp3+ Treg cells through a GPR30- and programmed death 1 (PD-1)-dependent mechanism. This novel finding was indicative of the protective effect of GPR30 activation in EAE and provides a strong foundation for the clinical application of GPR30 agonists such as G-1 in MS. However, future studies are needed to elucidate cross-signaling and evaluate possible additive effects of combined signaling through both GPR30 and ER-α. Deciphering the possible mechanism of involvement of GPR30 in estrogenmediated protection against EAE may result in lowering treatment doses of E2 and GPR30 agonists that could minimize risks and maximize immunoregulation and therapeutic effects in MS. Alternatively, one might envision using E2 derivatives with reduced estrogenic activity alone or in combination with GPR30 agonists as therapies for both male and female MS patients.

KW - 17β-estradiol

KW - Dendritic cells

KW - EAE

KW - Encephalitogenic t cells

KW - ER-α

KW - ER-β

KW - Estrogen

KW - G-1

KW - G-15

KW - GPR30

KW - IL-10

KW - IL-17

KW - Inflammation

KW - MS

KW - Tregs

UR - http://www.scopus.com/inward/record.url?scp=80055110340&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80055110340&partnerID=8YFLogxK

M3 - Article

AN - SCOPUS:80055110340

VL - 11

SP - 262

EP - 274

JO - Immunology, Endocrine and Metabolic Agents in Medicinal Chemistry

JF - Immunology, Endocrine and Metabolic Agents in Medicinal Chemistry

SN - 1871-5222

IS - 4

ER -