1 Lung Immunology Group, Infectious Disease and Immunity, Department of Medicine, Imperial College London, London, United Kingdom.
2 MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom; and.
Am J Respir Cell Mol Biol. 2018 Nov;59(5):557-571. doi: 10.1165/rcmb.2018-0007OC.
IL-8-dependent inflammation is a hallmark of host lung innate immunity to bacterial pathogens, yet in many human lung diseases, including chronic obstructive pulmonary disease, bronchiectasis, and pulmonary fibrosis, there are progressive, irreversible, pathological changes associated with elevated levels of IL-8 in the lung. To better understand the duality of IL-8-dependent host immunity to bacterial infection and lung pathology, we expressed human IL-8 transgenically in murine bronchial epithelium, and investigated the impact of overexpression on lung bacterial clearance, host immunity, and lung pathology and function. Persistent IL-8 expression in bronchial epithelium resulted in neutrophilia, neutrophil maturation and activation, and chemotaxis. There was enhanced protection against challenge with Pseudomonas aeruginosa, and significant changes in baseline expression of innate and adaptive immunity transcripts for Ccl5, Tlr6, IL-2, and Tlr1. There was increased expression of Tbet and Foxp3 in response to the Pseudomonas antigen OprF, indicating a regulatory T-cell phenotype. However, this enhanced bacterial immunity came at a high price of progressive lung remodeling, with increased inflammation, mucus hypersecretion, and fibrosis. There was increased expression of Ccl3 and reduced expression of Claudin 18 and F11r, with damage to epithelial organization leading to leaky tight junctions, all of which resulted in impaired lung function with reduced compliance, increased resistance, and bronchial hyperreactivity as measured by whole-body plethysmography. These results show that IL-8 overexpression in the bronchial epithelium benefits lung immunity to bacterial infection, but specifically drives lung damage through persistent inflammation, lung remodeling, and damaged tight junctions, leading to impaired lung function.
IL-8 依赖性炎症是宿主肺部固有免疫对细菌病原体的标志，但在许多人类肺部疾病中，包括慢性阻塞性肺疾病、支气管扩张和肺纤维化，与肺部 IL-8 水平升高相关的进行性、不可逆转的病理变化。为了更好地理解 IL-8 依赖性宿主对细菌感染和肺部病理学的双重作用，我们在小鼠支气管上皮细胞中转基因表达了人 IL-8，并研究了过表达对肺部细菌清除、宿主免疫和肺部病理及功能的影响。支气管上皮细胞中持续的 IL-8 表达导致中性粒细胞增多、中性粒细胞成熟和激活以及趋化作用。对铜绿假单胞菌的挑战有增强的保护作用，并且先天和适应性免疫转录本的基线表达 Ccl5、Tlr6、IL-2 和 Tlr1 发生显著变化。对 Pseudomonas 抗原 OprF 的反应中 Tbet 和 Foxp3 的表达增加，表明存在调节性 T 细胞表型。然而，这种增强的细菌免疫是以进行性肺部重塑为代价的，伴有炎症增加、黏液分泌过多和纤维化。Ccl3 的表达增加，Claudin 18 和 F11r 的表达减少，上皮组织的损伤导致紧密连接渗漏，所有这些都导致肺功能受损，顺应性降低，阻力增加，通过全身 plethysmography 测量的支气管高反应性。这些结果表明，支气管上皮细胞中 IL-8 的过表达有益于肺部对细菌感染的免疫，但通过持续的炎症、肺部重塑和受损的紧密连接，特异性地导致肺部损伤，从而导致肺功能受损。
