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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.02740

ERα signaling increased IL-17A production in Th17 cells by upregulating IL-23R expression, mitochondrial respiration, and proliferation

 Hubaida Fuseini1, 2, Jacqueline-Yvonne Cephus3,  Pingsheng Wu3, J. B. Davis3, Diana C. Contreras2, Vivek Gandhi4, Jeffrey C. Rathmell2 and  Dawn C. Newcomb2, 3*
  • 1Vanderbilt University, United States
  • 2Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, United States
  • 3Department of Medicine, Vanderbilt University Medical Center, United States
  • 4Vanderbilt University Medical Center, United States

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.

Keywords: Th17, Estrogen (17β-estradiol), Estrogen receptor a (era), IL-17A, IL-23R, Oxygen consumption rate (OCR), cox20, Cytochrome C oxidase ( COX )

Received: 23 May 2019; Accepted: 08 Nov 2019.

Copyright: © 2019 Fuseini, Cephus, Wu, Davis, Contreras, Gandhi, Rathmell and Newcomb. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Mx. Dawn C. Newcomb, Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, 37232, Tennessee, United States, dawn.newcomb@vanderbilt.edu