Androgen signaling restricts glutaminolysis to drive sex-specific Th17 metabolism in allergic airway inflammation
Nowrin U. Chowdhury, … , Jeffrey C. Rathmell, Dawn C. Newcomb
Nowrin U. Chowdhury, … , Jeffrey C. Rathmell, Dawn C. Newcomb
Published October 15, 2024
Citation Information: J Clin Invest. 2024;134(23):e177242. https://doi.org/10.1172/JCI177242.
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Research Article Immunology Pulmonology

Androgen signaling restricts glutaminolysis to drive sex-specific Th17 metabolism in allergic airway inflammation

Abstract

Female individuals have an increased prevalence of many Th17 cell–mediated diseases, including asthma. Androgen signaling decreases Th17 cell–mediated airway inflammation, and Th17 cells rely on glutaminolysis. However, it remains unclear whether androgen receptor (AR) signaling modifies glutamine metabolism to suppress Th17 cell–mediated airway inflammation. We show that Th17 cells from male humans and mice had decreased glutaminolysis compared with female individuals, and that AR signaling attenuated Th17 cell mitochondrial respiration and glutaminolysis in mice. Using allergen-induced airway inflammation mouse models, we determined that females had a selective reliance upon glutaminolysis for Th17-mediated airway inflammation, and that AR signaling attenuated glutamine uptake in CD4+ T cells by reducing expression of glutamine transporters. In patients with asthma, circulating Th17 cells from men had minimal reliance upon glutamine uptake compared to Th17 cells from women. AR signaling thus attenuates glutaminolysis, demonstrating sex-specific metabolic regulation of Th17 cells with implications for Th17 or glutaminolysis targeted therapeutics.

Authors

Nowrin U. Chowdhury, Jacqueline-Yvonne Cephus, Emely Henriquez Pilier, Melissa M. Wolf, Matthew Z. Madden, Shelby N. Kuehnle, Kaitlin E. McKernan, Erin Q. Jennings, Emily N. Arner, Darren R. Heintzman, Channing Chi, Ayaka Sugiura, Matthew T. Stier, Kelsey Voss, Xiang Ye, Kennedi Scales, Evan S. Krystofiak, Vivek D. Gandhi, Robert D. Guzy, Katherine N. Cahill, Anne I. Sperling, R. Stokes Peebles Jr., Jeffrey C. Rathmell, Dawn C. Newcomb

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Figure 2

AR signaling in CD4+ T cells reduces Th17-driven neutrophilic inflammation during airway inflammation.

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AR signaling in CD4+ T cells reduces Th17-driven neutrophilic inflammati...
(A) Model of HDM allergen challenge. Female and male Arfl and Cd4Cre+ Ar fl mice were challenged intranasally with 40 μg of HDM 3 times per week for 3 weeks. BAL fluid and lungs were harvested 24 hours after the last challenge. (B) Quantification of eosinophils and neutrophils in the BAL fluid from mice after HDM challenge. (C) IL-13 and IL-17A protein expression in BAL fluid after HDM challenge. (D) Airway hyperresponsiveness as measured by FlexiVent with increasing doses of methacholine was also conducted on HDM-challenged female and male Arfl and Cd4Cre+ Arfl mice 48 hours after last challenge (Data show mean ± SEM, n = 4–6 mice per group). (E) Representative flow diagrams of IL-13+ Th2 cells and IL-17A+ Th17 cells. (F) Quantification of lung Th2 and Th17 cells after HDM challenge (G and H) Expression of GLUD1, Glut1, HIF1-α, and pS6 in lung Th2 cells (G) and Th17 cells (H) after HDM challenge. (B, C, and E–H) Data are expressed as mean ± SEM: n = 7–9 mice per group combined from 2 independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001; ANOVA with Tukey’s post hoc test. See Supplemental Figures 3, 4, and 5.