性激素影响ORMDL3表达：对性别相关哮喘表型的启示
2025/12/30
摘要
背景：鞘脂代谢相关的遗传多态性，特别是涉及类乳清黏蛋白3（ORMDL3）基因的变异，已被证实与哮喘风险相关。值得注意的是，哮喘的患病率与严重程度呈现出显著的性别差异，这种差异始于儿童期并持续至成年。然而，这种性别二态性背后的分子机制仍未完全阐明。
目的：旨在探究ORMDL3是否在气道功能及哮喘样特征的性别差异中发挥作用。
方法：测量了健康男女人体供者肺组织，以及在暴露于17β-雌二醇、屋尘螨主要变应原1（Der p 1）或两者兼具后的人支气管上皮细胞（BEAS-2B）中ORMDL3的表达水平。采用小鼠哮喘模型评估ORMDL3表达、气道反应性及气道重塑方面的性别依赖性差异。研究使用了药物调控雌激素信号通路及ORMDL3-鞘氨醇-1-磷酸（S1P）轴。方法包括qRT-PCR、免疫染色、液相色谱-串联质谱联用检测（LC-MS/MS）以及气道功能测量。
结果：女性肺组织显示出比男性更高的ORMDL3表达，且这与同一患者群体中较高的第一秒用力呼气容积占用力肺活量百分比（%FEV(1)/FVC）相关。在BEAS-2B细胞中，17β-雌二醇显著上调ORMDL3，并通过诱导神经酰胺酶、SphK1/2及S1P受体的表达改变了鞘脂代谢。Der p 1同样增加了ORMDL3表达并通过炎症小体信号触发上皮细胞活化，而雌二醇则增强了IFN-β信号及MUC5AC的表达。Der p 1与17β-雌二醇联合处理对鞘脂代谢、干扰素及炎症小体通路产生了协同激活效应。这些体外发现促使我们利用小鼠哮喘模型进行体内研究，结果显示雌性小鼠表现为ORMDL3、鞘氨醇及S1P水平升高，同时伴有气道高反应性（AHR）及气道重塑加剧。使用他莫昔芬或雌二醇治疗可跨性别地使AHR及S1P信号通路恢复正常。过敏原致敏加剧了偏向雌性的ORMDL3表达及气道炎症。抑制ORMDL3-S1P轴仅能减轻雌性小鼠的哮喘样特征。
结论：本研究确定ORMDL3是一个受雌激素响应的气道反应性调节因子，可能通过调控鞘脂代谢，介导哮喘特征的性别相关差异。
SEX HORMONES INFLUENCE ORMDL3 EXPRESSION: IMPLICATIONS FOR SEX-ASSOCIATED ASTHMA PHENOTYPE.
Elisabetta, Granato; Ida, Cerqua;
Abstrast
BACKGROUND: Genetic polymorphisms in sphingolipid metabolism, particularly involving the orosomucoid-like 3 (ORMDL3) gene, have been associated with asthma risk. Notably, asthma prevalence and severity exhibit pronounced sex differences, emerging in childhood and persisting into adulthood. However, the molecular mechanisms underlying this sexual dimorphism remain incompletely elucidated.
OBJECTIVE: To investigate whether ORMDL3 contributes to sex-differences in airway function and asthma-like features.
METHODS: ORMDL3 expression was measured in lung tissues from healthy male and female human donors and in human bronchial epithelial cells (BEAS-2B) following exposure to 17β-estradiol, Dermatophagoides pteronyssinus 1 (Der p 1), or both. A murine preparation of asthma was used to evaluate sex-dependent differences in ORMDL3 expression, airway responsiveness, and remodeling. Pharmacological modulation of estrogen signaling and the ORMDL3-sphingosine-1-phosphate (S1P) axis were employed. Methods included qRT-PCR, immunostaining, Liquid Chromatography coupled to tandem Mass Spectrometry detection (LC-MS/MS), and airway function measurements.
RESULTS: Female lungs exhibited higher ORMDL3 expression than males, and this correlated with elevated forced expiratory volume to forced vital capacity ratios (%FEV(1)/FVC) in the same patients. In BEAS-2B cells, 17β-estradiol significantly upregulated ORMDL3 and altered sphingolipid metabolism by inducing expression of ceramidase, SphK1/2, and S1P receptors. Der p 1 also increased ORMDL3 and triggered epithelial activation via inflammasome signaling, while estradiol enhanced IFN-β signaling and MUC5AC expression. Combination Derp 1/17β-estradiol synergistically activated sphingolipid, interferon, and inflammasome pathways. These in vitro findings prompted in vivo investigation using a murine asthma preparation, where female mice displayed elevated ORMDL3, sphingosine, and S1P levels, with increased airway hyperresponsiveness (AHR) and remodeling. Treatment with tamoxifen or estradiol normalized AHR and S1P signaling across sexes. Allergen sensitization intensified female-biased ORMDL3 expression and airway inflammation. Inhibition of the ORMDL3-S1P axis attenuated asthma-like features only in females.
CONCLUSION: This study identifies ORMDL3 as an estrogen responsive regulator of airway responsiveness that may contribute to sex-related differences in asthma features through modulation of sphingolipid metabolism.
背景：鞘脂代谢相关的遗传多态性，特别是涉及类乳清黏蛋白3（ORMDL3）基因的变异，已被证实与哮喘风险相关。值得注意的是，哮喘的患病率与严重程度呈现出显著的性别差异，这种差异始于儿童期并持续至成年。然而，这种性别二态性背后的分子机制仍未完全阐明。
目的：旨在探究ORMDL3是否在气道功能及哮喘样特征的性别差异中发挥作用。
方法：测量了健康男女人体供者肺组织，以及在暴露于17β-雌二醇、屋尘螨主要变应原1（Der p 1）或两者兼具后的人支气管上皮细胞（BEAS-2B）中ORMDL3的表达水平。采用小鼠哮喘模型评估ORMDL3表达、气道反应性及气道重塑方面的性别依赖性差异。研究使用了药物调控雌激素信号通路及ORMDL3-鞘氨醇-1-磷酸（S1P）轴。方法包括qRT-PCR、免疫染色、液相色谱-串联质谱联用检测（LC-MS/MS）以及气道功能测量。
结果：女性肺组织显示出比男性更高的ORMDL3表达，且这与同一患者群体中较高的第一秒用力呼气容积占用力肺活量百分比（%FEV(1)/FVC）相关。在BEAS-2B细胞中，17β-雌二醇显著上调ORMDL3，并通过诱导神经酰胺酶、SphK1/2及S1P受体的表达改变了鞘脂代谢。Der p 1同样增加了ORMDL3表达并通过炎症小体信号触发上皮细胞活化，而雌二醇则增强了IFN-β信号及MUC5AC的表达。Der p 1与17β-雌二醇联合处理对鞘脂代谢、干扰素及炎症小体通路产生了协同激活效应。这些体外发现促使我们利用小鼠哮喘模型进行体内研究，结果显示雌性小鼠表现为ORMDL3、鞘氨醇及S1P水平升高，同时伴有气道高反应性（AHR）及气道重塑加剧。使用他莫昔芬或雌二醇治疗可跨性别地使AHR及S1P信号通路恢复正常。过敏原致敏加剧了偏向雌性的ORMDL3表达及气道炎症。抑制ORMDL3-S1P轴仅能减轻雌性小鼠的哮喘样特征。
结论：本研究确定ORMDL3是一个受雌激素响应的气道反应性调节因子，可能通过调控鞘脂代谢，介导哮喘特征的性别相关差异。
（中日友好医院呼吸与危重症医学科 万静萱 摘译 林江涛 审校）
（J Allergy Clin Immunol 2025 Dec 6;(0). DOI:10.1016/j.jaci.2025.10.035. IF: 10.228）
SEX HORMONES INFLUENCE ORMDL3 EXPRESSION: IMPLICATIONS FOR SEX-ASSOCIATED ASTHMA PHENOTYPE.
Elisabetta, Granato; Ida, Cerqua;
Abstrast
BACKGROUND: Genetic polymorphisms in sphingolipid metabolism, particularly involving the orosomucoid-like 3 (ORMDL3) gene, have been associated with asthma risk. Notably, asthma prevalence and severity exhibit pronounced sex differences, emerging in childhood and persisting into adulthood. However, the molecular mechanisms underlying this sexual dimorphism remain incompletely elucidated.
OBJECTIVE: To investigate whether ORMDL3 contributes to sex-differences in airway function and asthma-like features.
METHODS: ORMDL3 expression was measured in lung tissues from healthy male and female human donors and in human bronchial epithelial cells (BEAS-2B) following exposure to 17β-estradiol, Dermatophagoides pteronyssinus 1 (Der p 1), or both. A murine preparation of asthma was used to evaluate sex-dependent differences in ORMDL3 expression, airway responsiveness, and remodeling. Pharmacological modulation of estrogen signaling and the ORMDL3-sphingosine-1-phosphate (S1P) axis were employed. Methods included qRT-PCR, immunostaining, Liquid Chromatography coupled to tandem Mass Spectrometry detection (LC-MS/MS), and airway function measurements.
RESULTS: Female lungs exhibited higher ORMDL3 expression than males, and this correlated with elevated forced expiratory volume to forced vital capacity ratios (%FEV(1)/FVC) in the same patients. In BEAS-2B cells, 17β-estradiol significantly upregulated ORMDL3 and altered sphingolipid metabolism by inducing expression of ceramidase, SphK1/2, and S1P receptors. Der p 1 also increased ORMDL3 and triggered epithelial activation via inflammasome signaling, while estradiol enhanced IFN-β signaling and MUC5AC expression. Combination Derp 1/17β-estradiol synergistically activated sphingolipid, interferon, and inflammasome pathways. These in vitro findings prompted in vivo investigation using a murine asthma preparation, where female mice displayed elevated ORMDL3, sphingosine, and S1P levels, with increased airway hyperresponsiveness (AHR) and remodeling. Treatment with tamoxifen or estradiol normalized AHR and S1P signaling across sexes. Allergen sensitization intensified female-biased ORMDL3 expression and airway inflammation. Inhibition of the ORMDL3-S1P axis attenuated asthma-like features only in females.
CONCLUSION: This study identifies ORMDL3 as an estrogen responsive regulator of airway responsiveness that may contribute to sex-related differences in asthma features through modulation of sphingolipid metabolism.
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