Androgen Signaling Restricts Glutaminolysis to Drive Sex-Specific Th17 Metabolism

Females have increased prevalence of many Th17-mediated diseases. While androgen signaling decreases Th17-mediated inflammation, the mechanisms are not fully understood. Th17 cells rely on glutaminolysis; however, it remains unclear whether androgen receptor (AR) signaling in males modifies glutamine metabolism to suppress Th17-mediated inflammation. We show that Th17 cells from male humans and mice had decreased glutaminolysis compared to females, and AR signaling attenuated Th17 cell mitochondrial respiration and glutaminolysis. Using allergen-induced airway inflammation models, we determined females, but not males, had a critical reliance upon glutaminolysis for Th17-mediated airway inflammation, and AR signaling attenuated glutamine uptake by reducing expression of glutamine transporters. These findings were confirmed in circulating human Th17 cells with minimal reliance on glutamine uptake in male compared to female Th17 cells. We found that AR signaling attenuates glutaminolysis, demonstrating sex-specific metabolic regulation of Th17 cells with implications for design and implementation of Th17 or glutaminolysis targeted therapeutics. Highlights ### Competing Interest Statement J.C.R. is a founder, scientific advisory board member, and stockholder of Sitryx Therapeutics; a scientific advisory board member and stockholder of Caribou Biosciences; a member of the scientific advisory board of Nirogy Therapeutics; has consulted for Merck, Pfizer, and Mitobridge within the past 3 years; and has received research support from Incyte Corp., Calithera Biosciences, and Tempest Therapeutics.