Estrogen receptor alpha signaling in dendritic cells modulates autoimmune disease phenotype in mice

Estrogen is a disease-modifying factor in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) via estrogen receptor alpha (ER alpha). However, the mechanisms by which ER alpha signaling contributes to changes in disease pathogenesis have not been completely elucidated. Here, we demonstrate that ER alpha 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 (IFN beta), a first-line MS treatment. Estrogen synthesized by extragonadal sources is crucial for controlling disease phenotypes. Mechanistically, activated ER alpha 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 IFN beta components. Diminished ER alpha signaling in DCs generates neurotoxic effector CD4(+) T cells via mLT-lymphotoxin beta receptor (LT beta R) signaling. Lymphotoxin beta receptor antagonist abolished EAE disease symptoms in the DC-specific ER alpha-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.