Title : Estrogen Receptor Alpha (ER?) signaling in dendritic cells modulates autoimmune encephalomyelitis disease phenotype in mice
Abstract:
Estrogen is a disease-modifying factor in multiple sclerosis (MS), and its animal model, the 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, using the EAE murine model of MS, we demonstrated that the knockout of ERα resulted in altered EAE phenotypes characterized by prolonged motor dysfunctions. For instance, ERα−/− EAE mice presented with motor dysfunction slightly earlier than wild-type (WT) mice. On the contrary, while the severity of motor impairment in WT EAE mice remitted at ~30 dpi, EAE disease in ERα−/− EAE mice did not taper and instead was sustained up to 50 dpi. ERα−/− EAE mice showed severe neurodegeneration in the central nervous system (CNS) and resistance to interferon beta (IFNβ), a first-line MS treatment. Moreover, EAE-induced in WT and aromatase (CYP19)-deficient (Cyp19−/−) mice were treated with IFNβ or vehicle (PBS). DC-specific ERα knockout mice express high levels of membrane lymphotoxin (mLT) and interferon beta (IFNβ). Furthermore, dendritic cells (DC)-specific ERα knockout mice express high levels of membrane lymphotoxin (mLT) and IFNβ and show severe and prolonged disease. In vitro, we showed that estrogen signaling via ERα exerts its disease-modifying effect in EAE via direct modulation of TLR-4 immune cell effector function by repressing the TRAF3-IRF3 pathway downstream of TLR4 activation in DCs. Mechanistically, activated ERα directly interacts with TRAF3, a TLR4 downstream signaling molecule, to degrade TRAF3 via ubiquitination, which eventually suppresses IRF3 nuclear translocation and the subsequent transcription of membrane lymphotoxin (mLT) and IFNβ components. Diminished ERα signaling generates neurotoxic effector CD4+ T cells via mLT- lymphotoxin beta receptor (LTβR) signaling. Collectively, these findings indicate that DC-specific ERα functions determine the EAE disease phenotype via controlling TRAF3-mediated cytokines production in DCs.
Audience Take Away
- The therapeutic target of endogenous estrogens could be a therapeutics for MS
- This data can help others to investigate the role of endogenous estrogen on the pathogenesis of neurodegenerative and neuroinflammatory CNS diseases other than MS
