Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia, USA.
J Infect Dis. 2021 Oct 13;224(7):1225-1235. doi: 10.1093/infdis/jiab188.
Chronic granulomatous disease (CGD) results from deficiency of nicotinamide adenine dinucleotide phosphate(NADPH) oxidase and impaired reactive oxygen species (ROS) generation. This leads to impaired killing of Aspergillus and, independently, a pathologic hyperinflammatory response to the organism. We hypothesized that neutrophil-derived ROS inhibit the inflammatory response to Aspergillus and that acute lung injury in CGD is due to failure of this regulation. Mice with gp91phox deficiency, the most common CGD mutation, had more severe lung injury, increased neutrophilinfiltration, and increased lung tumor necrosis factor (TNF) after Aspergillus challenge compared with wild-types. Neutrophils were surprisingly the predominant source of TNF in gp91phox-deficient lungs. TNF neutralization inhibited neutrophil recruitment in gp91phox-deficient mice and protected from lung injury. We propose that, in normal hosts, Aspergillus stimulates TNF-dependent neutrophil recruitment to the lungs and neutrophil-derived ROS limit inflammation. In CGD, in contrast, recruited neutrophils are the dominant source of TNF, promoting further neutrophil recruitment in a pathologic positive-feedback cycle, resulting in progressive lung injury.
慢性肉芽肿病（CGD）是由于烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶缺乏和活性氧（ROS）生成受损引起的。这导致曲霉菌的杀伤能力受损，并且独立地导致对该生物体的病理性过度炎症反应。我们假设中性粒细胞衍生的 ROS 抑制了对曲霉菌的炎症反应，并且 CGD 中的急性肺损伤是由于这种调节失败引起的。与野生型相比，具有 gp91phox 缺乏症（CGD 最常见的突变）的小鼠在曲霉菌攻击后具有更严重的肺损伤、增加的中性粒细胞浸润和增加的肺肿瘤坏死因子（TNF）。令人惊讶的是，中性粒细胞是 gp91phox 缺陷肺中 TNF 的主要来源。TNF 中和抑制了 gp91phox 缺陷小鼠中的中性粒细胞募集，并防止了肺损伤。我们提出，在正常宿主中，曲霉菌刺激 TNF 依赖性中性粒细胞向肺部募集，而中性粒细胞衍生的 ROS 限制了炎症。相比之下，在 CGD 中，募集的中性粒细胞是 TNF 的主要来源，在病理性正反馈循环中促进进一步的中性粒细胞募集，导致进行性肺损伤。
