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IL23 Promotes Antimicrobial Pathways in Human Macrophages, Which Are Reduced With the IBD-Protective IL23R R381Q Variant.
Cellular and Molecular Gastroenterology and Hepatology ( IF 7.2 ) Pub Date : 2020-05-29 , DOI: 10.1016/j.jcmgh.2020.05.007
Rui Sun 1 , Clara Abraham 1
Affiliation  

Background & Aims

Interleukin (IL)23 is a major contributor to inflammatory bowel disease (IBD) pathogenesis and is being pursued as a therapeutic target, both through targeting IL23 alone or in combination with IL12. Unexpected trial outcomes highlight the importance of understanding the cell types through which IL23 regulates immune responses, and how IL23 and IL12 compare in these responses. Macrophages are key players in IBD, and IL23 recently was found to promote inflammatory outcomes in human macrophages. This raises the possibility that IL23 may be required for additional essential macrophage functions, in particular microbial clearance, such that either blocking the IL23 pathway or the IL23R–R381Q IBD-protective variant may reduce macrophage-mediated microbial clearance.

Methods

We analyzed protein expression, signaling, bacterial uptake, and intracellular bacterial clearance in human monocyte-derived macrophages through Western blot, flow cytometry, and gentamicin protection.

Results

Autocrine/paracrine IL23 was critical for optimal levels of pattern-recognition-receptor (PRR)-induced intracellular bacterial clearance in human macrophages. Mechanisms regulated by IL23 included induction of pyruvate dehydrogenase kinase 1-dependent bacterial uptake, and up-regulation of reactive oxygen species through nicotinamide adenine dinucleotide phosphate oxidase members, nitric oxide synthase 2, and autophagy through ATG5 and ATG16L1. Complementing these pathways in IL23R-deficient macrophages restored PRR-induced bacterial uptake and clearance. Janus kinase 2, TYK2, and STAT3 were required for IL23-induced mechanisms. IL23 and IL12 induced antimicrobial pathways to similar levels in human macrophages. Relative to IL23R–R381, transfected IL23R–Q381, or monocyte-derived macrophages from IL23R–Q381 carriers showed reduced bacterial uptake and clearance.

Conclusions

We identify that autocrine/paracrine IL23 is required for optimal PRR-enhanced macrophage bacterial uptake and intracellular bacterial clearance, define mechanisms regulating IL23R-induced bacterial clearance, and determine how the IBD-protective IL23R–R381Q variant modulates these processes.



中文翻译:

IL23 促进人类巨噬细胞中的抗微生物途径,而 IBD 保护性 IL23R R381Q 变体可减少这种途径。

背景与目标

白细胞介素 (IL)23 是炎症性肠病 (IBD) 发病机制的主要促成因素,并且正在通过单独靶向 IL23 或与 IL12 结合作为治疗靶点而寻求。意外的试验结果强调了了解 IL23 调节免疫反应的细胞类型的重要性,以及 IL23 和 IL12 在这些反应中的比较。巨噬细胞是 IBD 的关键参与者,最近发现 IL23 可促进人类巨噬细胞的炎症结果。这增加了 IL23 可能需要额外的重要巨噬细胞功能的可能性,特别是微生物清除,因此阻断 IL23 途径或 IL23R-R381Q IBD 保护性变体可能会减少巨噬细胞介导的微生物清除。

方法

我们通过蛋白质印迹、流式细胞术和庆大霉素保护分析了人单核细胞衍生的巨噬细胞中的蛋白质表达、信号传导、细菌摄取和细胞内细菌清除。

结果

自分泌/旁分泌 IL23 对于人类巨噬细胞中模式识别受体 (PRR) 诱导的细胞内细菌清除的最佳水平至关重要。IL23 调控的机制包括诱导丙酮酸脱氢酶激酶 1 依赖的细菌摄取,通过烟酰胺腺嘌呤二核苷酸磷酸氧化酶成员、一氧化氮合酶 2 上调活性氧,以及通过 ATG5 和 ATG16L1 进行自噬。在 IL23R 缺陷型巨噬细胞中补充这些途径可恢复 PRR 诱导的细菌摄取和清除。Janus 激酶 2、TYK2 和 STAT3 是 IL23 诱导机制所必需的。IL23 和 IL12 在人类巨噬细胞中诱导抗菌途径达到相似水平。相对于 IL23R-R381,转染的 IL23R-Q381,

结论

我们确定自分泌/旁分泌 IL23 是最佳 PRR 增强的巨噬细胞细菌摄取和细胞内细菌清除所必需的,定义了调节 IL23R 诱导的细菌清除的机制,并确定了 IBD 保护性 IL23R–R381Q 变体如何调节这些过程。

更新日期:2020-05-29
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