1 Division of Pulmonary and Critical Care Medicine.
3 Center for Regenerative Medicine.
Am J Respir Cell Mol Biol. 2018 Dec;59(6):684-694. doi: 10.1165/rcmb.2017-0181OC.
The airway epithelial cell (AEC) response to allergens helps initiate and propagate allergic inflammation in asthma. CARMA3 is a scaffold protein that mediates G protein-coupled receptor-induced NF-κB activation in airway epithelium. In this study, we demonstrate that mice with CARMA3-deficient AECs have reduced airway inflammation, as well as reduced type 2 cytokine levels in response to Alternaria alternata. These mice also have reduced production of IL-33 and IL-25, and reduced numbers of innate lymphoid cells in the lung. We also show that CARMA3-deficient human AECs have decreased production of proasthmatic mediators in response to A. alternata. Finally, we show that CARMA3 interacts with inositol 1,4,5-trisphosphate receptors in AECs, and that inhibition of CARMA3 signaling reduces A. alternata-induced intracellular calcium release. In conclusion, we show that CARMA3 signaling in AECs helps mediate A. alternata-induced allergic airway inflammation, and that CARMA3 is an important signaling molecule for type 2 immune responses in the lung.
气道上皮细胞（AEC）对过敏原的反应有助于启动和促进哮喘中的过敏炎症。CARMA3 是一种支架蛋白，可介导气道上皮细胞中 G 蛋白偶联受体诱导的 NF-κB 激活。在这项研究中，我们证明 CARMA3 缺陷的 AEC 小鼠气道炎症减少，对Alternaria alternata 的反应中 2 型细胞因子水平降低。这些小鼠还减少了 IL-33 和 IL-25 的产生，以及肺中的固有淋巴细胞数量减少。我们还表明，CARMA3 缺陷的人 AEC 对 A. alternata 的反应中促哮喘介质的产生减少。最后，我们表明 CARMA3 在 AEC 中与肌醇 1,4,5-三磷酸受体相互作用，并且 CARMA3 信号通路的抑制减少了 A. alternata 诱导的细胞内钙释放。总之，我们表明 AEC 中的 CARMA3 信号有助于介导 A. alternata 诱导的过敏气道炎症，并且 CARMA3 是肺中 2 型免疫反应的重要信号分子。
