Irf4-dependent CD103+CD11b+ dendritic cells and the intestinal microbiome regulate monocyte and macrophage activation and intestinal peristalsis in postoperative ileus

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Abstract

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.

Detaljer

Författare
  • Judith Mira Pohl
  • Sebastian Gutweiler
  • Stephanie Thiebes
  • Julia K. Volke
  • Ludger Klein-Hitpass
  • Denise Zwanziger
  • Matthias Gunzer
  • Steffen Jung
  • William W. Agace
  • Christian Kurts
  • Daniel Robert Engel
Enheter & grupper
Externa organisationer
  • University of Duisburg-Essen
  • University of Bonn
  • University Hospital Essen
  • Weizmann Institute of Science Israel
  • Technical University of Denmark
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Immunologi inom det medicinska området

Nyckelord

Originalspråkengelska
Sidor (från-till)2110-2120
TidskriftGut
Volym66
Utgivningsnummer12
Tidigt onlinedatum2017 jun 23
StatusPublished - 2017
PublikationskategoriForskning
Peer review utfördJa