Objective Postoperative ileus (POI), the most frequent complication after intestinal surgery, depends on dendritic cells (DCs) and macrophages. Here, we have investigated the mechanism that activates these cells and the contribution of the intestinal microbiota for POI induction. Design POI was induced by manipulating the intestine of mice, which selectively lack DCs, monocytes or macrophages. The disease severity in the small and large intestine was analysed by determining the distribution of orally applied fluorescein isothiocyanate-dextran and by measuring the excretion time of a retrogradely inserted glass ball. The impact of the microbiota on intestinal peristalsis was evaluated after oral antibiotic treatment. Results We found that Cd11c-Cre+ Irf4flox/flox mice lack CD103+CD11b+ DCs, a DC subset unique to the intestine whose function is poorly understood. Their absence in the intestinal muscularis reduced pathogenic inducible nitric oxide synthase (iNOS) production by monocytes and macrophages and ameliorated POI. Pathogenic iNOS was produced in the jejunum by resident Ly6C– macrophages and infiltrating chemokine receptor 2-dependent Ly6C+ monocytes, but in the colon only by the latter demonstrating differential tolerance mechanisms along the intestinal tract. Consistently, depletion of both cell subsets reduced small intestinal POI, whereas the depletion of Ly6C+ monocytes alone was sufficient to prevent large intestinal POI. The differential role of monocytes and macrophages in small and large intestinal POI suggested a potential role of the intestinal microbiota. Indeed, antibiotic treatment reduced iNOS levels and ameliorated POI. Conclusions Our findings reveal that CD103+CD11b+ DCs and the intestinal microbiome are a prerequisite for the activation of intestinal monocytes and macrophages and for dysregulating intestinal motility in POI.

中文翻译：

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Irf4 依赖性 CD103 + CD11b + 树突状细胞和肠道微生物组调节术后肠梗阻中的单核细胞和巨噬细胞活化以及肠道蠕动

目的 术后肠梗阻 (POI) 是肠道手术后最常见的并发症，依赖于树突状细胞 (DC) 和巨噬细胞。在这里，我们研究了激活这些细胞的机制以及肠道微生物群对 POI 诱导的贡献。设计 POI 是通过操纵小鼠肠道诱导的，小鼠选择性缺乏 DC、单核细胞或巨噬细胞。通过测定口服异硫氰酸荧光素-葡聚糖的分布和测量逆行插入的玻璃球的排泄时间来分析小肠和大肠的疾病严重程度。口服抗生素治疗后评估微生物群对肠道蠕动的影响。结果 我们发现 Cd11c-Cre+ Irf4flox/flox 小鼠缺乏 CD103+CD11b+ DCs，肠道特有的 DC 子集，其功能知之甚少。它们在肠肌层中的缺失减少了单核细胞和巨噬细胞产生的致病性诱导型一氧化氮合酶 (iNOS) 并改善了 POI。致病性 iNOS 由常驻 Ly6C– 巨噬细胞和浸润性趋化因子受体 2 依赖性 Ly6C+ 单核细胞在空肠中产生，但仅在结肠中由后者产生，后者在肠道中表现出不同的耐受机制。一致地，两个细胞亚群的消耗减少了小肠 POI，而单独的 Ly6C+ 单核细胞的消耗足以防止大肠 POI。单核细胞和巨噬细胞在小肠和大肠 POI 中的不同作用表明肠道微生物群的潜在作用。确实，抗生素治疗降低了 iNOS 水平并改善了 POI。结论 我们的研究结果表明，CD103+CD11b+DCs 和肠道微生物组是肠道单核细胞和巨噬细胞活化以及 POI 肠道运动失调的先决条件。