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.
- postoperative ileus
- monocyte-derived macrophages
- colony-stimulating factor 1.
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Contributors GF: acquisition of data, analysis and interpretation of data; drafting of the manuscript. MS, PJG-P, EL, GG, MDG, NS, EM, FDE, YE, DL, ZML and KAS: acquisition of data, analysis and interpretation of data. JAVG and DAH: provided essential material and critical revision of the manuscript. GM and GEB: study concept and design; interpretation of data; obtained funding.
Funding This work was supported by grants from the Research Foundation – Flanders (FWO): Odysseus program (G.0905.07) and FWO grant (G.0566.12N) to GEB, FWO grant (G.0D83.17N) to GM, FWO PhD fellowship to MDG and FWO postdoctoral research fellowships to GM and PJG.
Competing interests None declared.
Patient consent Not obtained as this study does not involve human subjects.
Ethics approval Animal Care and Animal Experiments Committee of the University of Leuven (Leuven, Belgium).
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement No additional unpublished data from the study are present.