Right on the Nose: IL-17C and Nasal Host Defense.
Right on the Nose: IL-17C and Nasal Host Defense.
复制标题
就在鼻子上：IL-17C 和鼻宿主防御。
DOI：
10.1165/rcmb.2019-0236ed
复制
发表时间：
2020
影响因子：
6.4
通讯作者：
Robinson,KevenM
中科院分区：
文献类型：
--
作者：
Zemke,AnnaC;Robinson,KevenM
铜绿假单胞菌是一种无处不在的环境生物，如此常见，以至于我们中的许多人在日常淋浴中吸入这种细菌。健康的鼻窦腔对铜绿假单胞菌感染具有高度抵抗力。当先天性上皮防御受损时，例如囊性纤维化或原发性纤毛运动障碍时，铜绿假单胞菌是引起慢性鼻窦炎的最常见生物体，慢性鼻窦炎是这两种疾病几乎普遍的并发症。环境细菌菌株对鼻窦腔的感染可能是囊性纤维化中呼吸道感染的起始部位，并且肺移植后，驻留在鼻窦腔中的铜绿假单胞菌可能接种同种异体移植物。尽管鼻窦腔可能在慢性下呼吸道感染的发生中起着重要作用，但与肺部相比，关于鼻内上皮对革兰氏阴性病原体的反应知之甚少。更好地了解鼻窦腔中对革兰氏阴性病原体的先天防御将有助于我们更好地针对囊性纤维化和睫状体疾病中的铜绿假单胞菌进行预防和早期根除策略。在本期杂志中，Jeon及其同事（pp. 95-103）描述了鼻上皮细胞-P。铜绿假单胞菌共培养模型（1）。使用这个模型，他们表明IL-17 C在鼻上皮细胞中被铜绿假单胞菌高度诱导。上皮IL-17 C应答有助于模型中铜绿假单胞菌的清除，并且还导致脂质运载蛋白-2（LCN 2）的上调表达，其螯合某些类别的细菌铁载体，从而降低细菌铁摄取。IL-17 C是IL-17家族的功能上不同的成员，其通过IL 17-RA/IL 17-RE受体复合物在富含上皮的组织中以自分泌/旁分泌方式发出信号。在支气管上皮细胞中，聚肌胞苷酸、鞭毛蛋白、LPS和完整细菌（包括铜绿假单胞菌）可有效刺激IL-17 C产生（2，3）。支气管上皮中IL-17 C的表达增加见于多种疾病状态，包括囊性纤维化（3）。先前在嗜酸性鼻窦炎小鼠模型中证实了鼻上皮产生IL-17 C，并且与对照受试者相比，在慢性鼻窦炎个体的鼻粘膜样品中观察到IL-17 C表达增加;然而，IL-17 C在鼻防御中的作用知之甚少（4，5）。当Jeon及其同事沉默IL-17 C或受体IL-17 RE时，在共培养模型中观察到铜绿假单胞菌的生长增加。用重组IL-17 C预处理限制铜绿假单胞菌生长。有趣的是，作者显示了在共培养物中LCN 2的诱导，其随着IL-17 C的沉默而丧失。LCN 2由多种细胞类型产生，包括上皮细胞和骨髓细胞，并被多种细胞因子上调，包括IL-17 A，IL-22和IL-1b;因此，当骨髓来源的细胞存在时，可能存在其他调节机制。LCN 2在机体防御和铁代谢等生物学过程中发挥重要作用，其主要功能之一是限制细菌对铁的吸收。铁可能是铜绿假单胞菌慢性肺部感染过程中唯一最具生长限制性的营养素。因此，人类宿主和细菌之间存在持续的铁竞争，战斗双方都有防御和反防御。细菌铁载体是分泌的小分子，其以高亲和力结合铁并被细菌吸收。LCN 2可以螯合一些铁载体，从而防止细菌再摄取。铁载体在结构上是多样的，LCN 2主要是...
Pseudomonas aeruginosa is a ubiquitous environmental organism, so common that many of us inhale this bacterium aerosolized in our daily shower. The healthy sinonasal cavity is highly resistant to infection by P. aeruginosa. When innate epithelial defenses are impaired, for example in cystic fibrosis or primary ciliary dyskinesia, P. aeruginosa is the most common organism causing chronic rhinosinusitis, a near-universal complication of both diseases. Infection of the sinonasal cavity by environmental bacterial strains may be the initiating site of respiratory infection in cystic fibrosis, and after lung transplantation, P. aeruginosa resident in the sinonasal cavity may seed the allograft. Despite the likelihood that the sinonasal cavity plays a prominent role in the establishment of chronic lower respiratory infections, relatively little is known regarding the epithelial response to gram-negative pathogens in the nose as compared with the lung. A better understanding of innate defenses against gram-negative pathogens in the sinonasal cavity would help us better target prevention and early eradication strategies for P. aeruginosa in cystic fibrosis and ciliary diseases. In this issue of the Journal, Jeon and colleagues (pp. 95–103) describe a nasal epithelial cell–P. aeruginosa coculture model (1). Using this model, they show that IL-17C is highly induced in the nasal epithelial cells by P. aeruginosa. The epithelial IL-17C response contributes to the clearance of P. aeruginosa in the model and also leads to upregulated expression of lipocalin-2 (LCN2), which sequesters some classes of bacterial siderophores, thereby decreasing bacterial iron uptake. IL-17C is a functionally distinct member of the IL-17 family, which signals in an autocrine/paracrine fashion in epithelium-rich tissue through the IL17-RA/IL17-RE receptor complex. In bronchial epithelial cells, polyinosinic: polycytidylic acid, flagellin, LPS, and intact bacteria, including P. aeruginosa, potently stimulate IL-17C production (2, 3). Increased expression of IL-17C in the bronchial epithelium is seen in a variety of disease states, including cystic fibrosis (3). Nasal epithelial production of IL-17C was previously demonstrated in a mouse model of eosinophilic rhinosinusitis, and increased IL-17C expression was seen in nasal mucosal samples from individuals with chronic rhinosinusitis compared with control subjects; however, the roles of IL-17C in nasal defense are poorly understood (4, 5). When either IL-17C or the receptor IL-17RE was silenced by Jeon and colleagues, increased growth of P. aeruginosa was seen in the coculture model. Pretreatment with recombinant IL-17C restricted P. aeruginosa growth. Interestingly, the authors show induction of LCN2 in the coculture, which is lost with silencing of IL-17C. LCN2 is produced by multiple cell types, including epithelial and myeloid cells, and is upregulated by numerous cytokines, including IL-17A, IL-22, and IL-1b; thus, additional regulatory mechanisms may exist when myeloid-derived cells are present. LCN2 has roles in different biologic processes, including host defense and iron metabolism.One main function of LCN2 is to limit bacterial access to iron. Iron is possibly the single most growth-limiting nutrient during chronic lung infections with P. aeruginosa. Thus, there is ongoing competition between the human host and the bacterium for iron, with defenses and counterdefenses on both sides of the battle. Bacterial siderophores are secreted small molecules that bind iron with high affinity and are taken back up by the bacterium. LCN2 can sequester some siderophores, thereby preventing bacterial reuptake. Siderophores are structurally diverse, and LCN2 mainly …