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首页> 外文期刊>Archives of Toxicology >Membrane microdomains regulate NLRP10-and NLRP12-dependent signalling in A549 cells challenged with cigarette smoke extract
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Membrane microdomains regulate NLRP10-and NLRP12-dependent signalling in A549 cells challenged with cigarette smoke extract

机译：用卷烟烟雾提取挑战，在A549细胞中调节NLRP10和NLRP12依赖的信号传导

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Chronic obstructive pulmonary disease (COPD) is predicted to become the third leading cause of death and disability worldwide by 2030; with cigarette smoking (active or passive) being one of the chief cause of its occurrence. Cigarette smoke exposure has been found to result in excessive inflammation and tissue injury, which might lead to COPD, although the exact pathophysiology of the disease remains elusive. While previous studies have demonstrated the role of membrane-bound Toll-like receptors (TLRs) in cigarette smoke (CS)-induced inflammation, scant information is available about the role of cytosolic NOD-like receptors (NLRs) in regulating CS-mediated inflammatory responses. Thus, we investigated the role of NLRP10 and NLRP12 in regulating inflammatory responses in human alveolar type II epithelial cells (A549) and human monocytic cells (THP-1) in response to a challenge with cigarette smoke extract (CSE). We observed CSE-mediated increase in caspase-1 activity; production of IL-1 beta and IL-18; and expression of NLRP10 and NLRP12 in A549 and THP-1 cells. Interestingly, immunofluorescence imaging results demonstrated an increase in the membrane recruitment of NLRP10 and NLRP12 proteins in CSE-challenged A549 cells. We also observed an increase in the expression of lipid raft proteins (caveolin-1, caveolin-2, and flotillin-1) and an induction of lipid raft assembly following CSE-exposure in A549 cells. Lipid rafts are cholesterol-rich membrane microdomains well known to act as harbours for signalling molecules. Here we demonstrate the recruitment of NLRP10 and NLRP12 in lipid raft entities as well as the interaction of NLRP12 with the lipid raft protein caveolin-1 in CSE-challenged A549 cells. Furthermore, enrichment of lipid raft entities with poly-unsaturated fatty acids (PUFA) rescued A549 cells from CSE-mediated membrane recruitment of NLRP10 and NLRP12, and also from inflammatory responses and inflammasome activation. Enrichment of membrane microdomains with PUFA was able to reverse filipin (chemical agent used for disrupting lipid rafts)-mediated enhanced inflammation in CSE-challenged A549 cells. Overall, our findings unveil a novel mechanism by identifying an important role of membrane microdomains (lipid rafts) in regulating CSE-induced inflammation and NLRP10/NLRP12-dependent signalling in A549 cells.
机译：预计慢性阻塞性肺病（COPD）将成为2030年全球死亡和残疾的第三个主要原因;吸烟（活跃或被动）是其发生的主要原因之一。已经发现香烟烟雾暴露导致过度的炎症和组织损伤，这可能导致COPD，尽管该疾病的确切病理生理学仍然难以捉摸。虽然先前的研究表明膜结合的Toll样受体（TLRS）在香烟烟雾（CS）诱导的炎症中的作用，但是缩小信息可用于调节CS介导的CS介导的炎症中的细胞溶质点状受体（NLRS）的作用回应。因此，我们研究了NLRP10和NLRP12的作用，以应对香烟烟雾提取物（CSE）的攻击来调节人肺泡II型上皮细胞（A549）和人单核细胞（THP-1）中的炎症反应。我们观察到CSPase-1活性的CSE介导的增加;生产IL-1 Beta和IL-18;和A549和THP-1细胞中NLRP10和NLRP12的表达。有趣的是，免疫荧光成像结果表明，CSE攻击A549细胞中NLRP10和NLRP12蛋白的膜募集增加。我们还观察到脂质筏蛋白（Caveolin-1，Caveolin-2和Flotillin-1）表达的增加，以及在A549细胞中CSE暴露后的脂质筏组件的诱导。脂质筏是富含胆固醇的膜微膜，众所周知，充当信号分子的港口。在这里，我们证明了在CSE挑战A549细胞中募集脂质筏实体中NLRP10和NLRP12的NLRP10和NLRP12以及NLRP12与脂质筏蛋白Cavolin-1的相互作用。此外，具有聚不饱和脂肪酸（PUFA）的脂质筏实体富集来自CSE介导的NLRP10和NLRP12的CSE介导的膜募集的A549细胞，以及炎症反应和炎症性活化。富含PUFA的膜微瘤的富集能够逆转粉丝（用于破坏脂质筏的化学试剂）介导的CSE挑战A549细胞中的增强炎症。总体而言，我们的发现通过鉴定膜微膜（脂质筏）在调节CSE诱导的炎症和NLRP10 / NLRP12依赖性信号传导中的重要作用，揭示了一种新机制。

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