雌激素受体Alpha和糖皮质激素受体的双重激活使CRTh2介导的2型炎症上调；驱动女性哮喘严重性的机制？
2022/10/17
摘要
背景：2型高表型哮喘的特点是循环Th2细胞和嗜酸性粒细胞水平升高，这些细胞表达Th2细胞上表达的趋化性同源受体（CRTh2）。严重的哮喘在女性中比男性更常见；然而，潜在的机制仍然难以捉摸。这里我们研究了严重哮喘和2型炎症之间的关系是否因性别而异，以及雌激素是否影响Th2细胞对糖皮质激素（GC）的反应。
方法：评估了哮喘患者（n = 66）全血中的2型炎症和血液中Th2细胞（CD4+ CRTh2+ ）的比例。研究了GC和雌激素受体alpha（ERα）激动剂对体外分化的Th2细胞的影响。通过流式细胞仪、qRT-PCR、Western blot和ELISA测定CRTh2、2型细胞因子的表达和细胞凋亡的程度（Annexin V+ , 7-AAD）。
结果：在严重的哮喘中，女性的循环Th2细胞的比例和住院率都高于男性。患有严重哮喘的女性也比患有轻度/中度哮喘的女性有更多的Th2细胞和血清IL-13。Th2细胞、嗜酸性粒细胞和CRTh2 mRNA与女性的哮喘控制相关的临床特征相关，但与男性无关。在体外，GC和ERα激动剂处理的Th2细胞比单独用GC处理的Th2细胞表现出更少的凋亡、更多的CRTh2以及CRTh2激活后的IL-5和IL-13。
结论：患有严重哮喘的女性的循环Th2细胞水平高于男性，这可能是由于雌激素改变了GC的作用，增强了Th2细胞的生存和2型细胞因子的产生。
Dual Activation of Estrogen Receptor Alpha and Glucocorticoid Receptor Upregulate CRTh2-Mediated Type 2 Inflammation; Mechanism Driving Asthma Severity in Women?
Vijeyakumaran, M., Al Jawhri, M., Fortunato, J., Solomon, L., Shrestha Palikhe, N., Vliagoftis, H., & Cameron, L.
Abstract
BACKGROUND:Type 2-high asthma is characterized by elevated levels of circulating Th2 cells and eosinophils, cells that express chemoattractant-homologous receptor expressed on Th2 cells (CRTh2). Severe asthma is more common in women than men; however, the underlying mechanism(s) remain elusive. Here we examined whether the relationship between severe asthma and type 2 inflammation differs by sex and if estrogen influences Th2 cell response to glucocorticoid (GC).
METHODS:Type 2 inflammation and the proportion of blood Th2 cells (CD4+ CRTh2+ ) were assessed in whole blood from subjects with asthma (n = 66). The effects of GC and estrogen receptor alpha (ERα) agonist on in vitro differentiated Th2 cells were examined. Expression of CRTh2, type 2 cytokines and degree of apoptosis (Annexin V+ , 7-AAD) were determined by flow cytometry, qRT-PCR, western blot and ELISA.
RESULTS:In severe asthma, the proportion of circulating Th2 cells and hospitalizations were higher in women than men. Women with severe asthma also had more Th2 cells and serum IL-13 than women with mild/moderate asthma. Th2 cells, eosinophils and CRTh2 mRNA correlated with clinical characteristics associated with asthma control in women but not men. In vitro, GC and ERα agonist treated Th2 cells exhibited less apoptosis, more CRTh2 as well as IL-5 and IL-13 following CRTh2 activation than Th2 cells treated with GC alone.
CONCLUSION:Women with severe asthma had higher levels of circulating Th2 cells than men, which may be due to estrogen modifying the effects of GC, enhancing Th2 cell survival and type 2 cytokine production.
背景：2型高表型哮喘的特点是循环Th2细胞和嗜酸性粒细胞水平升高，这些细胞表达Th2细胞上表达的趋化性同源受体（CRTh2）。严重的哮喘在女性中比男性更常见；然而，潜在的机制仍然难以捉摸。这里我们研究了严重哮喘和2型炎症之间的关系是否因性别而异，以及雌激素是否影响Th2细胞对糖皮质激素（GC）的反应。
方法：评估了哮喘患者（n = 66）全血中的2型炎症和血液中Th2细胞（CD4+ CRTh2+ ）的比例。研究了GC和雌激素受体alpha（ERα）激动剂对体外分化的Th2细胞的影响。通过流式细胞仪、qRT-PCR、Western blot和ELISA测定CRTh2、2型细胞因子的表达和细胞凋亡的程度（Annexin V+ , 7-AAD）。
结果：在严重的哮喘中，女性的循环Th2细胞的比例和住院率都高于男性。患有严重哮喘的女性也比患有轻度/中度哮喘的女性有更多的Th2细胞和血清IL-13。Th2细胞、嗜酸性粒细胞和CRTh2 mRNA与女性的哮喘控制相关的临床特征相关，但与男性无关。在体外，GC和ERα激动剂处理的Th2细胞比单独用GC处理的Th2细胞表现出更少的凋亡、更多的CRTh2以及CRTh2激活后的IL-5和IL-13。
结论：患有严重哮喘的女性的循环Th2细胞水平高于男性，这可能是由于雌激素改变了GC的作用，增强了Th2细胞的生存和2型细胞因子的产生。
(中日友好医院呼吸与危重症医学科 沈焜路 摘译 林江涛 审校)
(Allergy. 2022 Oct 7. DOI: 10.1111/all.15543)
(Allergy. 2022 Oct 7. DOI: 10.1111/all.15543)
Dual Activation of Estrogen Receptor Alpha and Glucocorticoid Receptor Upregulate CRTh2-Mediated Type 2 Inflammation; Mechanism Driving Asthma Severity in Women?
Vijeyakumaran, M., Al Jawhri, M., Fortunato, J., Solomon, L., Shrestha Palikhe, N., Vliagoftis, H., & Cameron, L.
Abstract
BACKGROUND:Type 2-high asthma is characterized by elevated levels of circulating Th2 cells and eosinophils, cells that express chemoattractant-homologous receptor expressed on Th2 cells (CRTh2). Severe asthma is more common in women than men; however, the underlying mechanism(s) remain elusive. Here we examined whether the relationship between severe asthma and type 2 inflammation differs by sex and if estrogen influences Th2 cell response to glucocorticoid (GC).
METHODS:Type 2 inflammation and the proportion of blood Th2 cells (CD4+ CRTh2+ ) were assessed in whole blood from subjects with asthma (n = 66). The effects of GC and estrogen receptor alpha (ERα) agonist on in vitro differentiated Th2 cells were examined. Expression of CRTh2, type 2 cytokines and degree of apoptosis (Annexin V+ , 7-AAD) were determined by flow cytometry, qRT-PCR, western blot and ELISA.
RESULTS:In severe asthma, the proportion of circulating Th2 cells and hospitalizations were higher in women than men. Women with severe asthma also had more Th2 cells and serum IL-13 than women with mild/moderate asthma. Th2 cells, eosinophils and CRTh2 mRNA correlated with clinical characteristics associated with asthma control in women but not men. In vitro, GC and ERα agonist treated Th2 cells exhibited less apoptosis, more CRTh2 as well as IL-5 and IL-13 following CRTh2 activation than Th2 cells treated with GC alone.
CONCLUSION:Women with severe asthma had higher levels of circulating Th2 cells than men, which may be due to estrogen modifying the effects of GC, enhancing Th2 cell survival and type 2 cytokine production.
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过敏性哮喘加重中的气道纤维蛋白形成级联:炎症和重塑的意义
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