Benzo(a)pyrene Enhanced Dermatophagoides Group 1 (Der f 1)-Induced TGFβ1 Signaling Activation Through the Aryl Hydrocarbon Receptor-RhoA Axis in Asthma.
Benzo(a)pyrene Enhanced Dermatophagoides Group 1 (Der f 1)-Induced TGFβ1 Signaling Activation Through the Aryl Hydrocarbon Receptor-RhoA Axis in Asthma.
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DOI：
10.3389/fimmu.2021.643260
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发表时间：
2021
影响因子：
7.3
通讯作者：
Liu Z
中科院分区：
文献类型：
--
作者：
Wang E;Tu W;Do DC;Xiao X;Bhatti SB;Yang L;Sun X;Xu D;Yang P;Huang SK;Gao P;Liu Z
我们之前已经证明，苯并(a)芘（BaP）与类皮肤病1组过敏原（Der f1）共暴露可增强Der f1诱导的气道炎症。然而，潜在的机制仍未确定。在这里，我们研究了BaP暴露在Der f1诱导的哮喘气道炎症中增强的分子机制。我们发现，BaP共暴露增强了Der f1诱导的人支气管上皮细胞（HBECs）和哮喘小鼠模型气道中tgf - β1的分泌和信号激活。此外，利用AhR-二恶英响应元件报告质粒测定了BaP单独暴露或与Der f1共暴露诱导芳烃受体（AhR）活性。在HBECs中，通过AhR拮抗剂CH223191或敲低AhR， BaP和Der f1共同暴露诱导的tgf - β1表达和信号激活减弱。此外，AhR敲低导致BaP和Der f1共暴露诱导的活性RhoA减少。法舒地尔（一种RhoA/ROCK抑制剂）抑制RhoA信号，抑制BaP和Der f1共暴露诱导的tgf - β1表达和信号激活。这在表达本构活性RhoA （RhoA- l63）或显性阴性RhoA （RhoA- n19）的HBECs中得到进一步证实。荧光素酶报告子分析显示，RhoA启动子区域AhR结合位点的启动子活性显著增加。抑制RhoA可抑制BaP和Der f1共暴露诱导的气道高反应性、th2相关气道炎症和哮喘中tgf - β1信号激活。我们的研究揭示了AhR-RhoA在调节tgf - β1表达和信号激活方面先前未被发现的功能轴，代表了过敏性哮喘的潜在治疗靶点。
We have previously demonstrated that benzo(a)pyrene (BaP) co-exposure with dermatophagoides group 1 allergen (Der f 1) can potentiate Der f 1-induced airway inflammation. The underlying mechanism, however, remains undetermined. Here we investigated the molecular mechanisms underlying the potentiation of BaP exposure on Der f 1-induced airway inflammation in asthma. We found that BaP co-exposure potentiated Der f 1-induced TGFβ1 secretion and signaling activation in human bronchial epithelial cells (HBECs) and the airways of asthma mouse model. Moreover, BaP exposure alone or co-exposure with Der f 1-induced aryl hydrocarbon receptor (AhR) activity was determined by using an AhR-dioxin-responsive element reporter plasmid. The BaP and Der f 1 co-exposure-induced TGFβ1 expression and signaling activation were attenuated by either AhR antagonist CH223191 or AhR knockdown in HBECs. Furthermore, AhR knockdown led to the reduction of BaP and Der f 1 co-exposure-induced active RhoA. Inhibition of RhoA signaling with fasudil, a RhoA/ROCK inhibitor, suppressed BaP and Der f 1 co-exposure-induced TGFβ1 expression and signaling activation. This was further confirmed in HBECs expressing constitutively active RhoA (RhoA-L63) or dominant-negative RhoA (RhoA-N19). Luciferase reporter assays showed prominently increased promoter activities for the AhR binding sites in the promoter region of RhoA. Inhibition of RhoA suppressed BaP and Der f 1 co-exposure-induced airway hyper-responsiveness, Th2-associated airway inflammation, and TGFβ1 signaling activation in asthma. Our studies reveal a previously unidentified functional axis of AhR–RhoA in regulating TGFβ1 expression and signaling activation, representing a potential therapeutic target for allergic asthma.
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DOI：
10.1016/j.jaci.2018.08.023
发表时间：
2019-04
期刊：
The Journal of allergy and clinical immunology
影响因子：
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2.5
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DOI：
10.1016/j.jaci.2018.04.042
发表时间：
2019-01
期刊：
The Journal of allergy and clinical immunology
影响因子：
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