Chowdhury Nowrin U, Cephus Jacqueline-Yvonne, Henriquez Pilier Emely, Wolf Melissa M, Madden Matthew Z, Kuehnle Shelby N, McKernan Kaitlin E, Jennings Erin Q, Arner Emily N, Heintzman Darren R, Chi Channing, Sugiura Ayaka, Stier Matthew T, Voss Kelsey, Ye Xiang, Scales Kennedi, Krystofiak Evan S, Gandhi Vivek D, Guzy Robert D, Cahill Katherine N, Sperling Anne I, Peebles R Stokes, Rathmell Jeffrey C, Newcomb Dawn C
Department of Pathology, Microbiology, and Immunology.
Vanderbilt Center for Immunobiology, and.
J Clin Invest. 2024 Oct 15;134(23):e177242. doi: 10.1172/JCI177242.
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.
女性个体患许多由辅助性T细胞17（Th17）介导的疾病（包括哮喘）的患病率更高。雄激素信号传导可减少Th17细胞介导的气道炎症，且Th17细胞依赖谷氨酰胺分解代谢。然而，雄激素受体（AR）信号传导是否通过改变谷氨酰胺代谢来抑制Th17细胞介导的气道炎症仍不清楚。我们发现，与女性相比，来自男性人类和小鼠的Th17细胞的谷氨酰胺分解代谢减少，并且AR信号传导减弱了小鼠Th17细胞的线粒体呼吸和谷氨酰胺分解代谢。使用变应原诱导的气道炎症小鼠模型，我们确定雌性对Th17介导的气道炎症有选择性地依赖谷氨酰胺分解代谢，并且AR信号传导通过降低谷氨酰胺转运蛋白的表达来减弱CD4 + T细胞对谷氨酰胺的摄取。在哮喘患者中，与女性的Th17细胞相比，男性循环中的Th17细胞对谷氨酰胺摄取的依赖性最小。因此，AR信号传导减弱了谷氨酰胺分解代谢，表明Th17细胞存在性别特异性代谢调节，这对靶向Th17或谷氨酰胺分解代谢的治疗具有重要意义。
