Type II alveolar epithelial cell-specific loss of RhoA exacerbates allergic airway inflammation through SLC26A4.
Type II alveolar epithelial cell-specific loss of RhoA exacerbates allergic airway inflammation through SLC26A4.
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II型肺泡上皮细胞特异性RhoA缺失通过SLC26A4加重过敏性呼吸道炎症。
DOI：
10.1172/jci.insight.148147
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发表时间：
2021-07-22
期刊：
影响因子：
8
通讯作者：
Gao P
中科院分区：
文献类型：
--
作者：
Do DC;Zhang Y;Tu W;Hu X;Xiao X;Chen J;Hao H;Liu Z;Li J;Huang SK;Wan M;Gao P
小G蛋白RhoA及其下游效应子是哮喘病理生理过程中的关键调节因子。然而，其内在机制仍不确定。在这里，我们用RhoA条件性KO小鼠（Sftpc-cre;RhoAfl/fl）在II型肺泡上皮细胞（AT 2）中产生哮喘小鼠模型，并证明AT 2细胞特异性RhoA缺失导致过敏原诱导的气道高反应性和气道炎症加剧，支气管肺泡灌洗液（BALF）中Th 2细胞因子升高。特别是，Sftpc-cre; RhoAfl/fl小鼠显示BALF和肺组织中TGF-β1水平显著降低，并且向小鼠施用重组TGF-β 1拯救了TGF-β1并减轻了在Sftpc-cre;RhoAfl/fl小鼠中观察到的增加的过敏性气道炎症。使用RNA测序技术，我们确定Slc 26 a4（pendrin），跨膜阴离子交换，作为RhoA缺陷型AT 2细胞中上调最多的基因。在哮喘患者和小鼠模型的AT 2细胞中以及在表达显性阴性RHOA（RHOA-N19）的人气道上皮细胞中进一步证实了SLC 26 A4的上调。支气管哮喘患者血清中SLA 26 A4水平升高，与1秒用力呼气容积百分比（FEV1%）呈负相关。此外，SLC 26 A4抑制促进上皮TGF-β1释放并减轻过敏性气道炎症。我们的研究揭示了AT 2细胞中的RhoA/SLC 26 A4轴作为对抗过敏性气道炎症的保护机制发挥作用。
The small GTPase RhoA and its downstream effectors are critical regulators in the pathophysiological processes of asthma. The underlying mechanism, however, remains undetermined. Here, we generated an asthma mouse model with RhoA–conditional KO mice (Sftpc-cre;RhoAfl/fl) in type II alveolar epithelial cells (AT2) and demonstrated that AT2 cell–specific deletion of RhoA leads to exacerbation of allergen-induced airway hyperresponsiveness and airway inflammation with elevated Th2 cytokines in bronchoalveolar lavage fluid (BALF). Notably, Sftpc-cre;RhoAfl/fl mice showed a significant reduction in Tgf-β1 levels in BALF and lung tissues, and administration of recombinant Tgf-β1 to the mice rescued Tgf-β1 and alleviated the increased allergic airway inflammation observed in Sftpc-cre;RhoAfl/fl mice. Using RNA sequencing technology, we identified Slc26a4 (pendrin), a transmembrane anion exchange, as the most upregulated gene in RhoA-deficient AT2 cells. The upregulation of SLC26A4 was further confirmed in AT2 cells of asthmatic patients and mouse models and in human airway epithelial cells expressing dominant-negative RHOA (RHOA-N19). SLA26A4 was also elevated in serum from asthmatic patients and negatively associated with the percentage of forced expiratory volume in 1 second (FEV1%). Furthermore, SLC26A4 inhibition promoted epithelial TGF-β1 release and attenuated allergic airway inflammation. Our study reveals a RhoA/SLC26A4 axis in AT2 cells that functions as a protective mechanism against allergic airway inflammation.
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发表时间：
2020-06-01
影响因子：
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