Testosterone Decreases House Dust Mite-Induced Type 2 and IL-17A-Mediated Airway Inflammation.
Testosterone Decreases House Dust Mite-Induced Type 2 and IL-17A-Mediated Airway Inflammation.
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DOI：
10.4049/jimmunol.1800293
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发表时间：
2018-10-01
期刊：
影响因子：
--
通讯作者：
Newcomb DC
中科院分区：
文献类型：
--
作者：
Fuseini H;Yung JA;Cephus JY;Zhang J;Goleniewska K;Polosukhin VV;Peebles RS Jr;Newcomb DC
作为成年人，女性患哮喘的可能性是男性的两倍;然而，解释这种性别差异的机制仍不清楚。增加的2型细胞因子和/或IL-17 A，分别导致气道嗜酸性粒细胞和嗜中性粒细胞增加，与哮喘相关。以往的研究表明，睾酮，通过雄激素受体（AR）的信号，减少Th 2介导的过敏性炎症和2型先天免疫反应在过敏性炎症。因此，我们假设睾酮和AR信号减弱2型和IL-17 A介导的气道炎症。为了检验我们的假设，假手术和性腺切除的雌性和雄性小鼠用屋尘螨（HDM）或载体（PBS）鼻内攻击3周。睾酮减少，卵巢激素增加HDM诱导的嗜酸性和嗜酸性炎症，IgE产生和气道高反应性，以及减少肺中IL-13+ CD 4 Th 2细胞和IL-17 A + CD 4 Th 17细胞的数量。接下来，使用不能通过AR发出信号的WT雄性和雌性小鼠以及ARtfm雄性小鼠，我们确定AR信号内在地减弱了IL-17 A + Th 17细胞，但通过抑制HDM诱导的IL-4产生间接地减少了肺中的IL-13+ CD 4 Th 2细胞。体外Th 2和Th 17细胞分化实验表明，AR信号对Th 2细胞分化无直接影响，但可降低Th 17细胞IL-17 A蛋白表达和IL-23受体mRNA相对表达。结合起来，这些发现表明AR信号通过不同的机制减弱了2型和IL-17 A炎症，并为女性哮喘患病率高于男性提供了潜在的解释。
As adults, women are twice as likely as men to have asthma; however, the mechanisms explaining this sexual dimorphism remain unclear. Increased type 2 cytokines and/or IL-17A, leading to increased airway eosinophils and neutrophils, respectively, are associated with asthma. Previous studies showed that testosterone, signaling through the androgen receptor (AR), decreased Th2-mediated allergic inflammation and type 2 innate immune responses during allergic inflammation. Therefore, we hypothesized that testosterone and AR signaling attenuates type 2 and IL-17A-mediated airway inflammation. To test our hypothesis, sham-operated and gonadectomized female and male mice were intranasally challenged with house dust mite (HDM) or vehicle (PBS) for 3 weeks. Testosterone decreased and ovarian hormones increased HDM-induced eosinophilic and neutrophilic inflammation, IgE production, and airway hyperresponsiveness, as well as decreased the numbers of IL-13+ CD4 Th2 cells and IL-17A+ CD4 Th17 cells in the lung. Next, using WT male and female mice and ARtfm male mice that are unable to signal through the AR, we determined AR signaling intrinsically attenuated IL-17A+ Th17 cells but indirectly decreased IL-13+ CD4 Th2 cells in the lung by suppressing HDM-induced IL-4 production. In vitro Th2 and Th17 differentiation experiments showed AR signaling had no direct effect on Th2 cell differentiation, but decreased IL-17A protein expression and IL-23 receptor mRNA relative expression from Th17 cells. Combined, these findings show AR signaling attenuated type 2 and IL-17A inflammation through different mechanisms and provide a potential explanation for the increased prevalence of asthma in women compared to men.
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DOI：
10.1164/rccm.200308-1094oc
发表时间：
2004-02-01
影响因子：
24.7
作者：
Johnson, JR;Wiley, RE;Jordana, M
通讯作者：
Jordana, M
影响因子：
1.9
作者：
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通讯作者：
Shah, A
DOI：
10.1016/j.jaci.2015.05.046
发表时间：
2015-10
期刊：
The Journal of allergy and clinical immunology
影响因子：
--
作者：
Newcomb DC;Cephus JY;Boswell MG;Fahrenholz JM;Langley EW;Feldman AS;Zhou W;Dulek DE;Goleniewska K;Woodward KB;Sevin CM;Hamilton RG;Kolls JK;Peebles RS Jr
通讯作者：
Peebles RS Jr
影响因子：
3.7
作者：
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通讯作者：
Morimoto, M
影响因子：
32.4
作者：
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通讯作者：
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