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

Abstract

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