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

Abstract

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.

Immature neutrophil signature associated with the sexual dimorphism of systemic juvenile idiopathic arthritis

“…have shown that neutrophils dimorphism may be modulated by adrenergic stimulation, and that isoprenaline, an adrenergic receptor agonist, binds more efficiently to female neutrophils 34 . In contrast, it is also known that autoimmunity is more prevalent in women, with a possible correlation with the generation of pathogenic Th17 CD4 lymphocytes capable of secreting GM‐CSF 35,36 . It is noteworthy that this has already been addressed in the collagen‐induced arthritis model in which female mice had more severe disease associated with higher frequencies of GM‐CSF‐secreting Th17 cells 37 .…”

Sex and Gender Aspects for Patient Stratification in Allergy Prevention and Treatment

“…Estrogen receptors α and β are expressed in CD4+ T lymphocytes, and their signaling enhances Th1 production of IFN-γ while show variable effects on Th2 production of IL-4 and Th17 production of IL-17A. Estrogen and progesterone increase Th17 cells expression of IL-23R and IL-17A production, as well as increase airway inflammation mediated by IL-17A [12]. [11].…”

“…while show variable effects on Th2 production of IL-4 and Th17 production of IL-17A. Estrogen and progesterone increase Th17 cells expression of IL-23R and IL-17A production, as well as increase airway inflammation mediated by IL-17A[12].…”

Implications of Sex Differences in Immunity for SARS-CoV-2 Pathogenesis and Design of Therapeutic Interventions

“…Immune cells furthermore have a critical role beyond host defense in regulating tissue regeneration ( Karin and Clevers, 2016 ; Vivier et al., 2018 ), ranging from ILCs, Th17 cells, and Th22 cells maintaining mucosal integrity ( Chung et al., 2012 ) to natural killer (NK) cells and macrophages shaping the architecture of the placenta ( Vento-Tormo et al., 2018 ). Frequencies of IL-22- and IL-17-producing RORɣt + CD4 + T cells are enhanced in women compared to men and have been shown to be regulated by sex hormones ( Fuseini et al., 2018 , 2019 ; Newcomb et al., 2015 ; Sankaran-Walters et al., 2013 ). IL-22 promotes epithelial stem cell proliferation via STAT3 signaling ( Lindemans et al., 2015 ), contributing to tissue resilience upon damage.…”