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, Jeffrey C Rathmell, Dawn C Newcomb
Author Information
Nowrin U Chowdhury: Department of Pathology, Microbiology, and Immunology.
Jacqueline-Yvonne Cephus: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Emely Henriquez Pilier: Department of Pathology, Microbiology, and Immunology.
Melissa M Wolf: Department of Pathology, Microbiology, and Immunology.
Matthew Z Madden: Department of Pathology, Microbiology, and Immunology.
Shelby N Kuehnle: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Kaitlin E McKernan: Department of Pathology, Microbiology, and Immunology.
Erin Q Jennings: Vanderbilt Center for Immunobiology, and.
Emily N Arner: Vanderbilt Center for Immunobiology, and.
Darren R Heintzman: Department of Pathology, Microbiology, and Immunology.
Channing Chi: Department of Pathology, Microbiology, and Immunology.
Ayaka Sugiura: Department of Pathology, Microbiology, and Immunology.
Matthew T Stier: Vanderbilt Center for Immunobiology, and.
Kelsey Voss: Department of Pathology, Microbiology, and Immunology.
Xiang Ye: Department of Pathology, Microbiology, and Immunology.
Kennedi Scales: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Evan S Krystofiak: Department of Cellular and Molecular Biology, Vanderbilt University, Nashville, Tennessee, USA.
Vivek D Gandhi: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Robert D Guzy: Department of Medicine, University of Wisconsin, Madison, Wisconsin, USA.
Katherine N Cahill: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Anne I Sperling: Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
R Stokes Peebles: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Jeffrey C Rathmell: Department of Pathology, Microbiology, and Immunology.
Dawn C Newcomb: Department of Pathology, Microbiology, and Immunology.
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.
