Androgen Signaling Restricts Glutaminolysis to Drive Sex-Specific Th17 Metabolism

Author:

Chowdhury Nowrin UORCID,Cephus Jacqueline-YvonneORCID,Madden Matthew ZORCID,Wolf Melissa M,Chi ChanningORCID,Sugiura AyakaORCID,Stier Matthew TORCID,Voss KelseyORCID,Ye Xiang,Kuehnle Shelby N,Scales Kennedi,Gandhi Vivek D,Guzy Robert D.ORCID,Cahill Katherine NORCID,Sperling Anne IORCID,Peebles R. StokesORCID,Rathmell Jeffrey CORCID,Newcomb Dawn CORCID

Abstract

SummaryFemales 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.HighlightsHuman male CD4+ T cells have decreased expression of metabolic enzymes and decreased reliance on glutaminolysis compared to female CD4+ T cells.Androgen signaling decreased mitochondrial metabolism in Th17 cells and decreased airway inflammation.Androgen signaling decreased glutamine uptake and utilization in Th17 cells.

Publisher

Cold Spring Harbor Laboratory

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