Colitis susceptibility in mice with reactive oxygen species deficiency is mediated by mucus barrier and immune defense defects
Colitis susceptibility in mice with reactive oxygen species deficiency is mediated by mucus barrier and immune defense defects
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DOI：
10.1038/s41385-019-0205-x
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发表时间：
2019-11-01
影响因子：
8
通讯作者：
Knaus, Ulla G.
中科院分区：
文献类型：
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作者：
Aviello, Gabriella;Singh, Ashish K.;Knaus, Ulla G.
NADPH 氧化酶 (NOX/DUOX) 产生的活性氧 (ROS) 提供抗菌防御、氧化还原信号传导和肠道屏障维护。失活的 NOX 变异与慢性肉芽肿性疾病（CGD；NOX2）和小儿炎症性肠病（IBD；NOX1）中的共病肠道炎症有关；然而，Nox 缺陷小鼠并不能反映人类疾病的易感性。在这里，我们评估了患者相关的低等位性 CGD 突变是否会增加小鼠肠道炎症的风险。 Cyba (P22(phox)) 突变小鼠产生较低的肠道 ROS，同时保持 Nox4 功能。 Cyba 变体导致粘液层严重破坏，细菌渗透到隐窝、菌群失调以及对入侵微生物的先天免疫反应受损，从而导致死亡。治疗耐药性 CGD 或儿科 IBD 所采用的方法（例如骨髓移植或口服抗生素治疗）可改善或预防小鼠的疾病。 Cyba 突变小鼠表型表明，ROS 缺乏导致肠道炎症发病机制中粘液屏障和有效先天免疫防御的丧失，支持联合打击模型，其中单一疾病变异会损害相互依赖的区室中的不同细胞功能。
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(phox)) 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.