UPR modulation of host immunity by Pseudomonas aeruginosa in cystic fibrosis.
UPR modulation of host immunity by Pseudomonas aeruginosa in cystic fibrosis.
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DOI：
10.1042/cs20200066
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发表时间：
2020-07-31
期刊：
影响因子：
--
通讯作者：
Sadikot RT
中科院分区：
文献类型：
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作者：
Bedi B;Lin KC;Maurice NM;Yuan Z;Bijli K;Koval M;Hart CM;Goldberg JB;Stecenko A;Sadikot RT
囊性纤维化（CF）是一种进行性多器官常染色体隐性遗传疾病，由于囊性纤维化跨膜电导调节因子（CFTR）基因的紊乱而对肺部造成破坏性影响。 CF 的发病率和死亡率主要是由粘膜纤毛清除受损、微生物感染和慢性炎症三联征引起的肺部并发症引起的。铜绿假单胞菌是 CF 感染大多数晚期患者的主要呼吸道病原体。尽管其临床影响已得到公认，但铜绿假单胞菌发病机制和宿主对铜绿假单胞菌感染的反应的分子机制仍不完全清楚。核激素受体过氧化物酶体增殖物激活受体 γ (PPARγ) 是炎症和宿主防御的重要调节剂，已被证明在 CF 气道中减少。在本研究中，我们试图研究抑制 PPARγ 表达的上游机制及其对气道上皮宿主防御的影响。内质网应激（ER 应激）触发由错误折叠的 CFTR 激活的未折叠蛋白反应（UPR），而铜绿假单胞菌感染导致 PPARγ 表达减弱。具体来说，PERK 信号通路导致 CCAAT 增强子结合蛋白同源蛋白 (CHOP) 的表达增强。 CHOP 诱导导致 PPARγ 表达的抑制。从机制上讲，我们发现CHOP诱导介导的PPARγ减弱，通过减少抗微生物肽（AMP）和对氧生酶-2（PON-2）的表达以及增强IL-8的表达，影响正常ΔF508初级气道上皮细胞以及支气管上皮细胞的先天免疫功能。此外，线粒体活性氧产生（mt-ROS）和内质网应激正前馈环路也会失调线粒体生物能。此外，我们的研究结果表明 PPARγ 激动剂吡格列酮 (PIO) 在多细胞水平上对宿主具有有益作用，从宿主防御到线粒体重新赋能。
Cystic fibrosis (CF) is a progressive multi organ autosomal recessive disease with devastating impact on the lungs caused by derangements of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Morbidity and mortality in CF are largely caused by lung complications due to the triad of impaired mucociliary clearance, microbial infections and chronic inflammation. P. aeruginosa is a main respiratory pathogen in individuals with CF infecting most patients in later stages. Despite its recognized clinical impact, the molecular mechanisms that underlie P. aeruginosa pathogenesis and the host response to P. aeruginosa infection remain incompletely understood. The nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARγ) an important modulator of inflammation and host defense, has shown to be reduced in CF airways. In this study we sought to investigate the upstream mechanisms repressing PPARγ expression and its impact on airway epithelial host defense. Endoplasmic Reticulum-stress (ER-stress) triggered unfolded protein response (UPR) activated by misfolded CFTR and P. aeruginosa infection contributed to attenuated expression of PPARγ. Specifically, the PERK signaling pathway lead to the enhanced expression of the CCAAT-enhancer-binding-protein homologous protein (CHOP). CHOP induction led to the repression of PPARγ expression. Mechanistically, we show that CHOP induction mediated PPARγ attenuation, impacted the innate immune function of normal, ΔF508 primary airway epithelial as well as bronchial epithelial cells by reducing expression of anti-microbial peptide (AMP) and paraoxanse-2 (PON-2), as well as enhancing IL-8 expression. Furthermore, mitochondrial reactive oxygen species production (mt-ROS) and ER stress positive feedforward loop also dysregulated mitochondrial bioenergetics. Additionally, our findings implicate that PPARγ agonist pioglitazone (PIO) has beneficial effect on the host at the multicellular level ranging from host defense to mitochondrial re-energization.