雄激素信号限制谷氨酰胺分解以驱动过敏性气道炎症中的性别特异性Th17代谢
2025/01/06
摘要
在许多Th17细胞介导的疾病（包括哮喘）中，女性具有更高的患病率。雄激素信号能减少Th17细胞介导的气道炎症，而Th17细胞依赖于谷氨酰胺分解。然而，目前尚不清楚雄激素受体（androgen receptor，AR）信号是否通过调节谷氨酰胺代谢来抑制Th17细胞介导的气道炎症。我们的研究表明，与女性/雌性相比，男性和雄性小鼠的Th17细胞的谷氨酰胺分解减少，并且AR信号减弱了小鼠中Th17细胞的线粒体呼吸和谷氨酰胺分解。利用过敏原诱导的气道炎症小鼠模型，我们发现雌性Th17介导的气道炎症对谷氨酰胺分解有选择性依赖，并且AR信号通过降低谷氨酰胺转运体的表达来减少CD4+ T细胞对谷氨酰胺的摄取。在哮喘患者的循环T细胞中，男性Th17细胞对谷氨酰胺摄取的依赖性也显著低于女性。因此，AR信号减弱了谷氨酰胺分解，证明了Th17细胞的性别特异性代谢调节，这对Th17或谷氨酰胺分解靶向治疗具有重要意义。
Androgen signaling restricts glutaminolysis to drive sex-specific Th17 metabolism in allergic airway inflammation
Chowdhury NU, Cephus JY, Henriquez Pilier E, Wolf MM, Madden MZ, Kuehnle SN, McKernan KE, Jennings EQ, Arner EN, Heintzman DR, Chi C, Sugiura A, Stier MT, Voss K, Ye X, Scales KL, Krystofiak ES, Gandhi VD, Guzy RD, Cahill KN, Sperling AI, Peebles RS Jr, Rathmell JC, Newcomb DC.
J Clin Invest. 2024 Oct 1:e177242. doi: 10.1172/JCI177242. Epub ahead of print. PMID: 39404231.
Abstract
Females 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 to females, and that AR signaling attenuated Th17 cell mitochondrial respiration and glutaminolysis in mice. Using allergen-induced airway inflammation mouse models, we determined females had a selective reliance upon glutaminolysis for Th17-mediated airway inflammation, and AR signaling attenuated glutamine uptake in CD4+ T cells by reducing expression of glutamine transporters. Minimal reliance on glutamine uptake in male Th17 cells compared to female Th17 cells was also found in circulating T cells from patients with asthma. AR signaling thus attenuates glutaminolysis, demonstrating sex-specific metabolic regulation of Th17 cells with implications for Th17 or glutaminolysis targeted therapeutics.
在许多Th17细胞介导的疾病（包括哮喘）中，女性具有更高的患病率。雄激素信号能减少Th17细胞介导的气道炎症，而Th17细胞依赖于谷氨酰胺分解。然而，目前尚不清楚雄激素受体（androgen receptor，AR）信号是否通过调节谷氨酰胺代谢来抑制Th17细胞介导的气道炎症。我们的研究表明，与女性/雌性相比，男性和雄性小鼠的Th17细胞的谷氨酰胺分解减少，并且AR信号减弱了小鼠中Th17细胞的线粒体呼吸和谷氨酰胺分解。利用过敏原诱导的气道炎症小鼠模型，我们发现雌性Th17介导的气道炎症对谷氨酰胺分解有选择性依赖，并且AR信号通过降低谷氨酰胺转运体的表达来减少CD4+ T细胞对谷氨酰胺的摄取。在哮喘患者的循环T细胞中，男性Th17细胞对谷氨酰胺摄取的依赖性也显著低于女性。因此，AR信号减弱了谷氨酰胺分解，证明了Th17细胞的性别特异性代谢调节，这对Th17或谷氨酰胺分解靶向治疗具有重要意义。
(四川大学华西医院呼吸与危重症医学科 杨倩1 王霁1 王刚1 译)
(J Clin Invest.2024 Oct 1:e177242.doi:10.1172/JCI177242. Epub ahead of print. PMID: 39404231.)
(J Clin Invest.2024 Oct 1:e177242.doi:10.1172/JCI177242. Epub ahead of print. PMID: 39404231.)
Androgen signaling restricts glutaminolysis to drive sex-specific Th17 metabolism in allergic airway inflammation
Chowdhury NU, Cephus JY, Henriquez Pilier E, Wolf MM, Madden MZ, Kuehnle SN, McKernan KE, Jennings EQ, Arner EN, Heintzman DR, Chi C, Sugiura A, Stier MT, Voss K, Ye X, Scales KL, Krystofiak ES, Gandhi VD, Guzy RD, Cahill KN, Sperling AI, Peebles RS Jr, Rathmell JC, Newcomb DC.
J Clin Invest. 2024 Oct 1:e177242. doi: 10.1172/JCI177242. Epub ahead of print. PMID: 39404231.
Abstract
Females 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 to females, and that AR signaling attenuated Th17 cell mitochondrial respiration and glutaminolysis in mice. Using allergen-induced airway inflammation mouse models, we determined females had a selective reliance upon glutaminolysis for Th17-mediated airway inflammation, and AR signaling attenuated glutamine uptake in CD4+ T cells by reducing expression of glutamine transporters. Minimal reliance on glutamine uptake in male Th17 cells compared to female Th17 cells was also found in circulating T cells from patients with asthma. AR signaling thus attenuates glutaminolysis, demonstrating sex-specific metabolic regulation of Th17 cells with implications for Th17 or glutaminolysis targeted therapeutics.
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