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 (ERa). However, the mechanisms by which ERa signaling contributes to changes in disease pathogenesis have not been completely elucidated. Here, we demonstrate that ERa 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 (IFNb), a firstline MS treatment. Estrogen synthesized by extragonadal sources is crucial for controlling disease phenotypes. Mechanistically, activated ERa 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 IFNb components. Diminished ERa signaling in DCs generates neurotoxic effector CD4 + T cells via mLTlymphotoxin beta receptor (LTbR) signaling. Lymphotoxin beta receptor antagonist abolished EAE disease symptoms in the DCspecific ERa-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.

The Impact of Microbiota–Immunity–Hormone Interactions on Autoimmune Diseases and Infection

“…Cytokines produced by the fetoplacental unit can modulate maternal immune responses, promoting a strong Th2 and decreasing Th1/Th17-mediated response to reduce the risks of miscarriage [ 172 , 173 ]. Estrogen/estrogen receptor (E2/ER) signaling plays an active role in the development, differentiation, and functionality of both innate and adaptive immune cells [ 174 , 175 , 176 ]. Indeed, a direct E2 role in regulating the function and differentiation of immune cells has been confirmed both in the healthy immune system and in several diseases [ 177 ].…”