Androgen signaling restricts glutaminolysis to drive sex-specific Th17 metabolism in allergic airway inflammation
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
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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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 3

AR signaling modifies mitochondrial metabolism but not glycolysis in Th17 cells.

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AR signaling modifies mitochondrial metabolism but not glycolysis in Th1...
(A) Seahorse MitoStress Test on differentiated Th17 cells from WT female, WT male, and ArTfm male mice to measure mitochondrial respiration using oxygen consumption rate (OCR) (n = 5 mice per group from 2 independent experiments). (B) Quantified measures of basal respiration, maximal respiration, and spare respiratory capacity from panel A. (C) Seahorse GlycoStress test on Th17 cells from WT female, WT male, and ArTfm male mice to measure glycolysis using extracellular acidification rate (ECAR) (n = 5–6 mice per group from 2 independent experiments). (D) Quantified measures of basal glycolysis, glycolytic capacity, and glycolytic reserve from panel C. (E and F) Expression of MitoSOX Red, a mitochondrial superoxide marker, and Mitotracker green (MTG), a stain to measure mitochondrial mass, in differentiated Th17 cells from WT female, WT male, and ArTfm male mice (n = 3–4 mice per group, representative of 2 independent experiments). Data show mean ± SEM, *P < 0.05, **P < 0.01; ANOVA with Tukey’s post hoc test. See Supplemental Figure 6 and 7.