IL-17A impairs host tolerance during airway chronic infection by Pseudomonas aeruginosa.
IL-17A impairs host tolerance during airway chronic infection by Pseudomonas aeruginosa.
复制标题
DOI：
10.1038/srep25937
复制
发表时间：
2016-05-18
影响因子：
4.6
通讯作者：
Bragonzi A
中科院分区：
文献类型：
--
作者：
Lorè NI;Cigana C;Riva C;De Fino I;Nonis A;Spagnuolo L;Sipione B;Cariani L;Girelli D;Rossi G;Basso V;Colombo C;Mondino A;Bragonzi A
抗性和耐受机制参与了寄主和病原菌之间的相互作用。IL-17介导的应答已被证明是宿主抵抗呼吸道感染的关键，而其在慢性气道定植期间宿主耐受性中的作用仍不清楚。在此，我们研究了在铜绿假单胞菌的气道慢性感染期间，IL-17介导的应答是否调节宿主耐受机制。首先，我们发现，在铜绿假单胞菌慢性感染的早期和晚期阶段，小鼠中的IL-17 A水平都是持续的，并在来自被铜绿假单胞菌感染的囊性纤维化患者的人类呼吸道样本中证实了这些观察结果。使用IL-17 a −/−或IL-17 ra −/−小鼠，我们发现IL-17 A/IL-17 RA轴的缺陷与：i）慢性感染和细菌负荷的发生率增加有关，表明其在宿主对铜绿假单胞菌的耐药性中的作用; ii）降低的细胞因子水平（KC）、组织先天免疫细胞和组织损伤标志物（pro-MMP-9，弹性蛋白降解，TGF-β1），证明宿主耐受性的改变。当慢性感染建立时，开始用单克隆抗体阻断IL-17 A活性，并没有改变宿主的抵抗力，但增加了耐受性。总之，本研究将IL-17介导的应答确定为铜绿假单胞菌慢性气道感染期间宿主耐受性的负调节因子。
Resistance and tolerance mechanisms participate to the interplay between host and pathogens. IL-17-mediated response has been shown to be crucial for host resistance to respiratory infections, whereas its role in host tolerance during chronic airway colonization is still unclear. Here, we investigated whether IL-17-mediated response modulates mechanisms of host tolerance during airways chronic infection by P. aeruginosa. First, we found that IL-17A levels were sustained in mice at both early and advanced stages of P. aeruginosa chronic infection and confirmed these observations in human respiratory samples from cystic fibrosis patients infected by P. aeruginosa. Using IL-17a−/− or IL-17ra−/− mice, we found that the deficiency of IL-17A/IL-17RA axis was associated with: i) increased incidence of chronic infection and bacterial burden, indicating its role in the host resistance to P. aeruginosa; ii) reduced cytokine levels (KC), tissue innate immune cells and markers of tissue damage (pro-MMP-9, elastin degradation, TGF-β1), proving alteration of host tolerance. Blockade of IL-17A activity by a monoclonal antibody, started when chronic infection is established, did not alter host resistance but increased tolerance. In conclusion, this study identifies IL-17-mediated response as a negative regulator of host tolerance during P. aeruginosa chronic airway infection.