Objective Postoperative ileus (POI) is assumed to result from myeloid cells infiltrating the intestinal muscularis externa (ME) in patients undergoing abdominal surgery. In the current study, we investigated the role of infiltrating monocytes in a murine model of intestinal manipulation (IM)-induced POI in order to clarify whether monocytes mediate tissue damage and intestinal dysfunction or they are rather involved in the recovery of gastrointestinal (GI) motility. Design IM was performed in mice with defective monocyte migration to tissues (C-C motif chemokine receptor 2, Ccr2−/ − mice) and wild-type (WT) mice to study the role of monocytes and monocyte-derived macrophages (MΦs) during onset and resolution of ME inflammation. Results At early time points, IM-induced GI transit delay and inflammation were equal in WT and Ccr2 − / − mice. However, GI transit recovery after IM was significantly delayed in Ccr2 − / − mice compared with WT mice, associated with increased neutrophil-mediated immunopathology and persistent impaired neuromuscular function. During recovery, monocyte-derived MΦs acquire pro-resolving features that aided in the resolution of inflammation. In line, bone marrow reconstitution and treatment with MΦ colony-stimulating factor 1 enhanced monocyte recruitment and MΦ differentiation and ameliorated GI transit in Ccr2 − / − mice. Conclusion Our study reveals a critical role for monocyte-derived MΦs in restoring intestinal homeostasis after surgical trauma. From a therapeutic point of view, our data indicate that inappropriate targeting of monocytes may increase neutrophil-mediated immunopathology and prolong the clinical outcome of POI, while future therapies should be aimed at enhancing MΦ physiological repair functions.

中文翻译：

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CCR2依赖性单核细胞衍生的巨噬细胞在术后肠梗阻中解决炎症并恢复肠道运动

目的 术后肠梗阻 (POI) 被认为是由接受腹部手术的患者的髓细胞浸润肠外肌层 (ME) 引起的。在目前的研究中，我们研究了浸润单核细胞在肠道操作 (IM) 诱导的 POI 小鼠模型中的作用，以阐明单核细胞是否介导组织损伤和肠道功能障碍，或者它们是否参与胃肠道 (GI) 的恢复运动性。在单核细胞向组织迁移有缺陷的小鼠（CC 基序趋化因子受体 2，Ccr2-/- 小鼠）和野生型 (WT) 小鼠中进行设计 IM，以研究单核细胞和单核细胞衍生的巨噬细胞 (MΦs) 在发病和ME炎症的消退。结果在早期时间点，IM 诱导的 GI 转运延迟和炎症在 WT 和 Ccr2 - / - 小鼠中相等。然而，与WT小鼠相比，IM后的胃肠道转运恢复在Ccr2 - / - 小鼠中显着延迟，与中性粒细胞介导的免疫病理学增加和神经肌肉功能持续受损有关。在恢复期间，单核细胞衍生的 MΦ 获得有助于消退炎症的促消退特征。一致地，骨髓重建和用 MΦ 集落刺激因子 1 处理增强了 Ccr2 - / - 小鼠的单核细胞募集和 MΦ 分化并改善了胃肠道转运。结论我们的研究揭示了单核细胞衍生的 MΦ 在手术创伤后恢复肠道稳态中的关键作用。从治疗的角度来看，我们的数据表明，不适当的单核细胞靶向可能会增加中性粒细胞介导的免疫病理学并延长 POI 的临床结果，