IRAK-M knockout promotes allergic airway inflammation, but not airway hyperresponsiveness, in house dust mite-induced experimental asthma model.
IRAK-M knockout promotes allergic airway inflammation, but not airway hyperresponsiveness, in house dust mite-induced experimental asthma model.
复制标题
在屋尘螨诱发的实验性哮喘模型中，IRAK-M 敲除会促进过敏性气道炎症，但不会导致气道高反应性
DOI：
10.21037/jtd-20-2133
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发表时间：
2021-03
影响因子：
2.5
通讯作者：
Gao J
中科院分区：
文献类型：
--
作者：
Zhang X;Zhang M;Li L;Chen W;Zhou W;Gao J
IL-1受体相关激酶(IRAK)-M由气道上皮细胞和巨噬细胞表达，在基于ova的动物模型中被证明可以调节急性和慢性气道炎症，表现出双相反应。屋尘螨（HDM）是现实生活中常见的空气过敏原，与哮喘发病密切相关。IRAK-M在hdm诱导的哮喘中的作用尚不清楚。本研究旨在通过IRAK-M敲除（KO）小鼠，探讨IRAK-M对HDM诱导的变应性气道炎症的影响及其可能的机制。用HDM致敏和激发野生型（WT）小鼠。使用多种细胞和分子生物学技术评估两种基因型小鼠在最后一次刺激后24小时气道炎症的差异。还进行了体外机制研究。HDM可显著上调WT小鼠肺组织中IRAK-M的表达。与WT对照组相比，hdm处理的IRAK-M KO小鼠气道炎症细胞（尤其是Th2细胞）浸润加剧，粘液分泌过量，支气管肺泡灌洗液中上皮介质IL-25、IL-33、TSLP和Th2细胞因子含量升高。肺IRAK-M - KO巨噬细胞表达更高比例的共刺激分子OX40L和cd80，并表现出增强的抗原摄取。而IRAK-M KO对HDM间接诱导的气道高反应性（AHR）无影响。研究结果表明，IRAK-M通过改变HDM刺激后肺巨噬细胞的活化和抗原摄取来保护过敏性气道炎症，而不是AHR。IRAK-M的最佳调控可能为过敏性气道炎症提供了一条有趣的治疗途径。
IL-1 receptor associated-kinase (IRAK)-M, expressed by airway epithelium and macrophages, was shown to regulate acute and chronic airway inflammation exhibiting a biphasic response in an OVA-based animal model. House dust mite (HDM) is a common real-life aeroallergen highly relevant to asthma pathogenesis. The role of IRAK-M in HDM-induced asthma remains unknown. This study was aimed to investigate the effect of IRAK-M on allergic airway inflammation induced by HDM using IRAK-M knockout (KO) mice and the potential underlying mechanisms. IRAK-M KO and wild-type (WT) mice were sensitized and challenged with HDM. The differences in airway inflammation were evaluated 24 hours after the last challenge between the two genotypes of mice using a number of cellular and molecular biological techniques. In vitro mechanistic investigation was also involved. Lung expression of IRAK-M was significantly upregulated by HDM in the WT mice. Compared with the WT controls, HDM-treated IRAK-M KO mice showed exacerbated infiltration of inflammatory cells, particularly Th2 cells, in the airways and mucus overproduction, higher epithelial mediators IL-25, IL-33 and TSLP and Th2 cytokines in bronchoalveolar lavage (BAL) fluid. Lung IRAK-M KO macrophages expressed higher percentage of costimulatory molecules OX40L and CD 80 and exhibited enhanced antigen uptake. However, IRAK-M KO didn’t impact the airway hyperreactivity (AHR) indirectly induced by HDM. The findings indicate that IRAK-M protects allergic airway inflammation, not AHR, by modifying activation and antigen uptake of lung macrophages following HDM stimulation. Optimal regulation of IRAK-M might indicate an intriguing therapeutic avenue for allergic airway inflammation.