P. aeruginosa tRNA-fMet halves secreted in outer membrane vesicles suppress lung inflammation in Cystic Fibrosis.
P. aeruginosa tRNA-fMet halves secreted in outer membrane vesicles suppress lung inflammation in Cystic Fibrosis.
复制标题
外膜囊泡中分泌的铜绿假单胞菌 tRNA-fMet 一半可抑制囊性纤维化中的肺部炎症。
DOI：
10.1101/2024.02.03.578737
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发表时间：
2024
期刊：
影响因子：
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通讯作者：
Stanton,BruceA
中科院分区：
文献类型：
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作者：
Li,Zhongyou;Barnaby,Roxanna;Nymon,Amanda;Roche,Carolyn;Koeppen,Katja;Ashare,Alix;Hogan,DeborahA;Gerber,ScottA;Taatjes,DouglasJ;Hampton,ThomasH;Stanton,BruceA
虽然妥布霉素可增加囊性纤维化（CSFCF）患者的肺功能，但妥布霉素只能适度降低肺内铜绿假单胞菌（P. aeruginosa）的密度;因此，妥布霉素改善肺功能的机制尚未完全了解。在这里，我们证明妥布霉素增加5′ tRNA-fMet的一半外膜囊泡（OMV）分泌的实验室和CF临床分离的P。铜绿。将5′ tRNA-fMet的一半从OMV转移到原代CF人支气管上皮细胞（CF-HBEC）中，减少OMV诱导的IL-8和IP-10分泌。在小鼠肺中，OMV中5′ tRNA-fMet半体表达增加减弱KC（IL-8的鼠同系物）分泌和中性粒细胞募集。此外，与停用妥布霉素相比，暴露于妥布霉素期间，从TCF中分离的支气管肺泡灌洗液中的IL-8和中性粒细胞较少。总之，我们在小鼠和CF-HBEC的体外研究中表明，妥布霉素通过增加OMV中5′ tRNA-fMet的一半来减少炎症，OMV被递送到CF-HBEC并减少IL-8和嗜酸性气道炎症。预计该效应可改善接受妥布霉素治疗的CIMCF患者的肺功能。本报告中的实验确定了一种新的机制，即妥布霉素在两种CF模型中减少炎症。妥布霉素增加了P分泌的OMV中tRNA-fMet的分泌。铜绿假单胞菌，这减少了CF-HBEC的原代培养物和小鼠肺中OMV-LPS诱导的炎症反应，这是一种预测减少CFNCF中肺损伤的作用。
Although tobramycin increases lung function in people with cystic fibrosis (pwCF), the density ofPseudomonas aeruginosa(P. aeruginosa) in the lungs is only modestly reduced by tobramycin; hence, the mechanism whereby tobramycin improves lung function is not completely understood. Here, we demonstrate that tobramycin increases 5′ tRNA-fMet halves in outer membrane vesicles (OMVs) secreted by laboratory and CF clinical isolates ofP. aeruginosa. The 5′ tRNA-fMet halves are transferred from OMVs into primary CF human bronchial epithelial cells (CF-HBEC), decreasing OMV-induced IL-8 and IP-10 secretion. In mouse lungs, increased expression of the 5′ tRNA-fMet halves in OMVs attenuated KC (murine homolog of IL-8) secretion and neutrophil recruitment. Furthermore, there was less IL-8 and neutrophils in bronchoalveolar lavage fluid isolated from pwCF during the period of exposure to tobramycin versus the period off tobramycin. In conclusion, we have shown in mice and in vitro studies on CF-HBEC that tobramycin reduces inflammation by increasing 5′ tRNA-fMet halves in OMVs that are delivered to CF-HBEC and reduce IL-8 and neutrophilic airway inflammation. This effect is predicted to improve lung function in pwCF receiving tobramycin forP. aeruginosainfection.NEW & NOTEWORTHYThe experiments in this report identify a novel mechanism, whereby tobramycin reduces inflammation in two models of CF. Tobramycin increased the secretion of tRNA-fMet halves in OMVs secreted byP. aeruginosa, which reduced the OMV-LPS-induced inflammatory response in primary cultures of CF-HBEC and in mouse lung, an effect predicted to reduce lung damage in pwCF.