Selective inhibition of estrogen receptor alpha restores regulatory T-cell function in autoimmune hepatitis

Abstract Dysfunction in regulatory T-cells (Tregs) is a hallmark of autoimmune hepatitis (AIH), serious hepatopathy often leading to end-stage liver damage and transplantation, if not treated. Treg impairment AIH has been linked defective response aryl hydrocarbon receptor (AhR) activation. AhR acts as modulator toxin adaptive immunity. We have previously shown that altered Tregs activation derives from heightened levels estrogen alpha (Erα), an non-canonical binding partner. In this study we investigated whether Erα selective antagonism modulates function AIH. Experiments were performed on immunomagnetically purified Tregs, exposed the Erα-specific antagonist methyl-piperidinopyrazole (MPP), combination with or without unconjugated bilirubin (UCB), known endogenous ligand. healthy controls (HC), UCB boosted ability suppress T-responder cell proliferation, was further increased when combined MPP. AIH, addition MPP significantly ameliorated suppress, UCB. Stimulation CYP1A1, CD39 IL-10 both HC. Analysis transcriptome indicated treatment CD73, ectoenzyme works tandem CD39, ultimately generate adenosine. conclusion, inhibition restores respond resulting suppressive This could provide new therapeutic strategy boost maintain immunotolerance Supported by grants NIH (R01 DK124408, R01 DK108894)