School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia.
Hunter Medical Research Institute, New Lambton Heights, NSW, Australia.
Mucosal Immunol. 2019 Jul;12(4):862-873. doi: 10.1038/s41385-019-0163-3. Epub 2019 Apr 11.
Extra-intestinal manifestations (EIM) are common in inflammatory bowel disease (IBD). One such EIM is sub-clinical pulmonary inflammation, which occurs in up to 50% of IBD patients. In animal models of colitis, pulmonary inflammation is driven by neutrophilic infiltrations, primarily in response to the systemic bacteraemia and increased bacterial load in the lungs. Platelet activating factor receptor (PAFR) plays a critical role in regulating pulmonary responses to infection in conditions, such as chronic obstructive pulmonary disease and asthma. We investigated the role of PAFR in pulmonary EIMs of IBD, using dextran sulfate sodium (DSS) and anti-CD40 murine models of colitis. Both models induced neutrophilic inflammation, with increased TNF and IL-1β levels, bacterial load and PAFR protein expression in mouse lungs. Antagonism of PAFR decreased lung neutrophilia, TNF, and IL-1β in an NLRP3 inflammasome-dependent manner. Lipopolysaccharide from phosphorylcholine (ChoP)-positive bacteria induced NLRP3 and caspase-1 proteins in human alveolar epithelial cells, however antagonism of PAFR prevented NLRP3 activation by ChoP. Amoxicillin reduced bacterial populations in the lungs and reduced NLRP3 inflammasome protein levels, but did not reduce PAFR. These data suggest a role for PAFR in microbial pattern recognition and NLRP3 inflammasome signaling in the lung.
肠外表现（EIM）在炎症性肠病（IBD）中很常见。其中一种 EIM 是亚临床性肺部炎症，在高达 50%的 IBD 患者中发生。在结肠炎的动物模型中，肺部炎症是由中性粒细胞浸润驱动的，主要是对系统性菌血症和肺部细菌负荷增加的反应。血小板激活因子受体（PAFR）在调节慢性阻塞性肺疾病和哮喘等疾病对感染的肺部反应中起着关键作用。我们使用葡聚糖硫酸钠（DSS）和抗 CD40 小鼠结肠炎模型，研究了 PAFR 在 IBD 的肺部 EIM 中的作用。这两种模型都诱导了中性粒细胞炎症，增加了 TNF 和 IL-1β 水平，肺部细菌负荷和 PAFR 蛋白表达。PAFR 拮抗剂以 NLRP3 炎性小体依赖性方式减少肺部中性粒细胞、TNF 和 IL-1β。来自磷酸胆碱（ChoP）阳性细菌的脂多糖诱导了人肺泡上皮细胞中的 NLRP3 和 caspase-1 蛋白，但 PAFR 拮抗剂阻止了 ChoP 对 NLRP3 的激活。阿莫西林减少了肺部的细菌种群并降低了 NLRP3 炎性小体蛋白水平，但没有降低 PAFR。这些数据表明 PAFR 在肺部的微生物模式识别和 NLRP3 炎性小体信号转导中起作用。
