@article{42742e2b43d041d7a1841522e2908434,
title = "Estrogen receptor alpha signaling in dendritic cells modulates autoimmune disease phenotype in mice",
abstract = "Estrogen is a disease-modifying factor in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) via estrogen receptor alpha (ERα). However, the mechanisms by which ERα signaling contributes to changes in disease pathogenesis have not been completely elucidated. Here, we demonstrate that ERα deletion in dendritic cells (DCs) of mice induces severe neurodegeneration in the central nervous system in a mouse EAE model and resistance to interferon beta (IFNβ), a first-line MS treatment. Estrogen synthesized by extragonadal sources is crucial for controlling disease phenotypes. Mechanistically, activated ERα directly interacts with TRAF3, a TLR4 downstream signaling molecule, to degrade TRAF3 via ubiquitination, resulting in reduced IRF3 nuclear translocation and transcription of membrane lymphotoxin (mLT) and IFNβ components. Diminished ERα signaling in DCs generates neurotoxic effector CD4+ T cells via mLT-lymphotoxin beta receptor (LTβR) signaling. Lymphotoxin beta receptor antagonist abolished EAE disease symptoms in the DC-specific ERα-deficient mice. These findings indicate that estrogen derived from extragonadal sources, such as lymph nodes, controls TRAF3-mediated cytokine production in DCs to modulate the EAE disease phenotype.",
keywords = "CNS neurodegenerative, estrogen, extragonadal organ, membrane lymphotoxin, phenotype change",
author = "Khaw, {Yee Ming} and Shehata Anwar and Jinyan Zhou and Tasuku Kawano and Lin, {Po Ching} and Ashley Otero and Radwa Barakat and Jenny Drnevich and Tomoko Takahashi and Ko, {Che Myong Jay} and Makoto Inoue",
note = "Funding Information: The authors would like to thank Mary Clutter, Eunjoo Kang, and Claire Cunningham for helping with sample isolation and analysis. The authors would like to thank Ms. Patricia Marie Jones (Associate Director for Research at Beckman Institute) for their editorial support of this manuscript. The authors would also like to thank Chris Wright and Alvaro G. Hernandez in Roy J. Carver Biotechnology Center at the University of Illinois at Urbana‐Champaign for RNA‐seq study. The MR1 tetramer technology was developed jointly by Dr. James McCluskey, Dr. Jamie Rossjohn, and Dr. David Fairlie, and the material was produced by the NIH Tetramer Core Facility as permitted to be distributed by the University of Melbourne. This research was supported by University of Illinois start‐up funds (MI). The authors declare no competing financial interests. Funding Information: The authors would like to thank Mary Clutter, Eunjoo Kang, and Claire Cunningham for helping with sample isolation and analysis. The authors would like to thank Ms. Patricia Marie Jones (Associate Director for Research at Beckman Institute) for their editorial support of this manuscript. The authors would also like to thank Chris Wright and Alvaro G. Hernandez in Roy J. Carver Biotechnology Center at the University of Illinois at Urbana-Champaign for RNA-seq study. The MR1 tetramer technology was developed jointly by Dr. James McCluskey, Dr. Jamie Rossjohn, and Dr. David Fairlie, and the material was produced by the NIH Tetramer Core Facility as permitted to be distributed by the University of Melbourne. This research was supported by University of Illinois start-up funds (MI). The authors declare no competing financial interests. Publisher Copyright: {\textcopyright} 2023 The Authors.",
year = "2023",
month = mar,
day = "6",
doi = "10.15252/embr.202154228",
language = "English (US)",
volume = "24",
journal = "EMBO Reports",
issn = "1469-221X",
publisher = "Nature Publishing Group",
number = "3",
}