LasR-deficient Pseudomonas aeruginosa variants increase airway epithelial mICAM-1 expression and enhance neutrophilic lung inflammation.
LasR-deficient Pseudomonas aeruginosa variants increase airway epithelial mICAM-1 expression and enhance neutrophilic lung inflammation.
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LASR缺陷型假单胞菌铜绿变体增加了气道上皮云母-1表达并增强嗜中性肺炎症。
DOI：
10.1371/journal.ppat.1009375
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发表时间：
2021-03
期刊：
影响因子：
6.7
通讯作者：
Nguyen D
中科院分区：
文献类型：
--
作者：
Hennemann LC;LaFayette SL;Malet JK;Bortolotti P;Yang T;McKay GA;Houle D;Radzioch D;Rousseau S;Nguyen D
铜绿假单胞菌引起慢性气道感染，这是囊性纤维化（CF）中肺部炎症和损伤的主要决定因素。功能丧失lasR突变体通常在慢性CF感染期间出现，与CF患者的肺功能加速下降相关，并在模型系统中诱导过度的嗜肺炎症。在这项研究中，我们研究了lasR突变体如何调节气道上皮细胞膜结合的ICAM-1（mICAM-1），表面粘附分子，并确定其在体外和体内对嗜酸性炎症的影响。我们证明，与野生型菌株相比，LasR缺陷型菌株诱导气道上皮细胞中mICAM-1水平升高，这一效应归因于LasR调节的蛋白酶对mICAM-1降解的丧失，并与增强的中性粒细胞粘附相关。在亚急性气道感染模型中，我们还观察到lasR muplatin感染的小鼠显示出更高的气道上皮ICAM-1表达和增加的嗜酸性肺部炎症。我们的研究结果为lasR突变体、lasR调节的蛋白酶和气道上皮ICAM-1表达之间的复杂相互作用提供了新的见解，并揭示了lasR突变体诱导的夸大炎症反应所涉及的新机制。囊性纤维化（CF）患者发展以慢性气道感染为特征的进行性肺病，其通常由机会性病原体铜绿假单胞菌引起，以及过度的非消退性嗜酸性炎症。lasR群体感应转录调节基因的功能缺失突变通常在慢性铜绿假单胞菌感染期间出现，并且与肺部炎症增加相关。在这项研究中，我们证明了在细胞培养物和小鼠感染模型中，与野生型铜绿假单胞菌菌株相比，功能丧失的lasR突变体诱导气道上皮细胞上mICAM-1水平增加。这种作用是由于LasR调节的分泌蛋白酶导致ICAM-1降解的损失，促进了中性粒细胞粘附，并与嗜中性粒细胞肺部炎症增加有关。我们的研究为铜绿假单胞菌-气道上皮-中性粒细胞相互作用提供了新的见解，并证明了铜绿假单胞菌的常见病理适应如何通过加剧炎症来推动肺部疾病的进展。
Pseudomonas aeruginosa causes chronic airway infections, a major determinant of lung inflammation and damage in cystic fibrosis (CF). Loss-of-function lasR mutants commonly arise during chronic CF infections, are associated with accelerated lung function decline in CF patients and induce exaggerated neutrophilic inflammation in model systems. In this study, we investigated how lasR mutants modulate airway epithelial membrane bound ICAM-1 (mICAM-1), a surface adhesion molecule, and determined its impact on neutrophilic inflammation in vitro and in vivo. We demonstrated that LasR-deficient strains induce increased mICAM-1 levels in airway epithelial cells compared to wild-type strains, an effect attributable to the loss of mICAM-1 degradation by LasR-regulated proteases and associated with enhanced neutrophil adhesion. In a subacute airway infection model, we also observed that lasR mutant-infected mice displayed greater airway epithelial ICAM-1 expression and increased neutrophilic pulmonary inflammation. Our findings provide new insights into the intricate interplay between lasR mutants, LasR-regulated proteases and airway epithelial ICAM-1 expression, and reveal a new mechanism involved in the exaggerated inflammatory response induced by lasR mutants. Cystic fibrosis (CF) patients develop progressive lung disease characterized by chronic airway infections, commonly caused by the opportunistic pathogen Pseudomonas aeruginosa, and excessive non-resolving neutrophilic inflammation. Loss of function mutations of the lasR quorum sensing transcription regulator gene commonly arise during chronic P. aeruginosa infections and are associated with increased lung inflammation. In this study, we demonstrated that loss-of-function lasR mutants induced increased mICAM-1 levels on airway epithelial cells compared to wild-type P. aeruginosa strains in cell culture and in murine infection models. This effect was caused by the loss of ICAM-1 degradation by LasR-regulated secreted protease, facilitated neutrophil adhesion, and was associated with increased neutrophilic lung inflammation. Our study provides novel insights into the P. aeruginosa—airway epithelial–neutrophil interactions, and demonstrates how a common pathoadaptation of P. aeruginosa may drive lung disease progression by exacerbating inflammation.
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