ERα Signaling Increased IL-17A Production in Th17 Cells by Upregulating IL-23R Expression, Mitochondrial Respiration, and Proliferation.

Journal Article (Journal Article)

Women have increased prevalence of Th17-mediated autoimmune diseases, including lupus and multiple sclerosis, and severe asthma. While estradiol and progesterone increased IL-17A production in Th17 cells by inhibiting Let7f miRNA expression and increasing IL-23 receptor (IL-23R) expression, it remained unclear how estrogen signaling through the canonical nuclear receptors, estrogen receptor α (ERα) and/or ERβ, regulated this pathway. We hypothesized that estrogen signaling through ERα increased IL-23R expression and IL-17A production from Th17 cells. To test this hypothesis, naïve T cells from WT female, WT male, Esr1 -/- and Esr2 -/- female mice were differentiated into Th17 cells. IL-17A production and IL-23R expression were significantly increased in Th17 cells from WT female mice compared to Th17 cells from WT male mice. Deletion of ERα (Esr1 -/-), but not ERβ (Esr2 -/-), significantly decreased IL-17A production and IL-23R expression in Th17 cells by limiting IL-23R expression in a Let-7f dependent manner. ERα deficiency also decreased Th17 cell proliferation as well as decreased T cell metabolism as measured by ATP-linked oxygen consumption rate and proton leakage. Further, we found that Cox20 expression, a protein involved in mitochondrial respiration through assembly of cytochrome c oxidase in the electron transport chain, was increased in Th17 cells from WT female mice compared to Th17 cells from WT male and Esr1 -/- female mice. Inhibition of Cox20 decreased IL-17 production in Th17 cells from WT female mice. Combined these studies showed that ERα signaling increased IL-17A production in Th17 cells by upregulating IL-23R expression and promoting mitochondrial respiration and proliferation.

Full Text

Duke Authors

Cited Authors

  • Fuseini, H; Cephus, J-Y; Wu, P; Davis, JB; Contreras, DC; Gandhi, VD; Rathmell, JC; Newcomb, DC

Published Date

  • 2019

Published In

Volume / Issue

  • 10 /

Start / End Page

  • 2740 -

PubMed ID

  • 31849948

Pubmed Central ID

  • PMC6892971

Electronic International Standard Serial Number (EISSN)

  • 1664-3224

Digital Object Identifier (DOI)

  • 10.3389/fimmu.2019.02740

Language

  • eng

Conference Location

  • Switzerland