Conway Institute, University College Dublin, Dublin, Ireland.
National Children's Research Center, Our Lady's Children's Hospital Crumlin, Dublin, Ireland.
Mucosal Immunol. 2019 Nov;12(6):1316-1326. doi: 10.1038/s41385-019-0205-x. Epub 2019 Sep 25.
Reactive oxygen species (ROS) generated by NADPH oxidases (NOX/DUOX) provide antimicrobial defense, redox signaling, and gut barrier maintenance. Inactivating NOX variants are associated with comorbid intestinal inflammation in chronic granulomatous disease (CGD; NOX2) and pediatric inflammatory bowel disease (IBD; NOX1); however Nox-deficient mice do not reflect human disease susceptibility. Here we assessed if a hypomorphic patient-relevant CGD mutation will increase the risk for intestinal inflammation in mice. Cyba (p22) mutant mice generated low intestinal ROS, while maintaining Nox4 function. The Cyba variant caused profound mucus layer disruption with bacterial penetration into crypts, dysbiosis, and a compromised innate immune response to invading microbes, leading to mortality. Approaches used in treatment-resistant CGD or pediatric IBD such as bone marrow transplantation or oral antibiotic treatment ameliorated or prevented disease in mice. The Cyba mutant mouse phenotype implicates loss of both mucus barrier and efficient innate immune defense in the pathogenesis of intestinal inflammation due to ROS deficiency, supporting a combined-hit model where a single disease variant compromises different cellular functions in interdependent compartments.
活性氧（ROS）由 NADPH 氧化酶（NOX/DUOX）产生，提供抗菌防御、氧化还原信号和肠道屏障维持。失活的 NOX 变体与慢性肉芽肿病（CGD；NOX2）和儿童炎症性肠病（IBD；NOX1）中的合并肠道炎症相关；然而，Nox 缺陷小鼠不能反映人类疾病易感性。在这里，我们评估了一种低功能相关性 CGD 突变是否会增加小鼠肠道炎症的风险。Cyba（p22）突变小鼠产生的肠道 ROS 水平较低，同时保持了 Nox4 功能。Cyba 变体导致粘液层严重破坏，细菌穿透隐窝，菌群失调，以及对入侵微生物的固有免疫反应受损，导致死亡。在治疗抵抗性 CGD 或儿科 IBD 中使用的方法，如骨髓移植或口服抗生素治疗，改善或预防了小鼠的疾病。Cyba 突变小鼠表型表明，由于 ROS 缺乏，粘液屏障和有效的固有免疫防御的丧失都参与了肠道炎症的发病机制，支持了一种联合打击模型，其中单个疾病变体损害了相互依赖的隔室中不同的细胞功能。
