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

Pohl, Judith Mira; Gutweiler, Sebastian; Thiebes, Stephanie; Volke, Julia K.; Klein-Hitpass, Ludger; Zwanziger, Denise; Gunzer, Matthias; Jung, Steffen; Agace, William W. LU and Kurts, Christian, et al. (2017) In Gut 66(12). p.2110-2120
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... (More)

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.

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published
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keywords
Immunity, Intestinal Monocytes and Macrophages, Dendritic cells, Microbiota, Postoperative Ileus
in
Gut
volume
66
issue
12
pages
2110 - 2120
publisher
BMJ Publishing Group
external identifiers
  • scopus:85026300363
  • wos:000416769400014
ISSN
0017-5749
DOI
10.1136/gutjnl-2017-313856
language
English
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yes
id
f9e0a3d4-91f4-47d1-ad0b-f1ce8e91ecd8
date added to LUP
2017-08-30 09:29:06
date last changed
2018-01-17 13:55:19
@article{f9e0a3d4-91f4-47d1-ad0b-f1ce8e91ecd8,
  abstract     = {<p>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<sup>+</sup> Irf4<sup>flox/flox</sup> mice lack CD103<sup>+</sup>CD11b<sup>+</sup> 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<sup>-</sup> macrophages and infiltrating chemokine receptor 2-dependent Ly6C<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup>CD11b<sup>+</sup> DCs and the intestinal microbiome are a prerequisite for the activation of intestinal monocytes and macrophages and for dysregulating intestinal motility in POI.</p>},
  author       = {Pohl, Judith Mira and Gutweiler, Sebastian and Thiebes, Stephanie and Volke, Julia K. and Klein-Hitpass, Ludger and Zwanziger, Denise and Gunzer, Matthias and Jung, Steffen and Agace, William W. and Kurts, Christian and Engel, Daniel Robert},
  issn         = {0017-5749},
  keyword      = {Immunity,Intestinal Monocytes and Macrophages, Dendritic cells,Microbiota,Postoperative Ileus},
  language     = {eng},
  month        = {06},
  number       = {12},
  pages        = {2110--2120},
  publisher    = {BMJ Publishing Group},
  series       = {Gut},
  title        = {Irf4-dependent CD103<sup>+</sup>CD11b<sup>+</sup> dendritic cells and the intestinal microbiome regulate monocyte and macrophage activation and intestinal peristalsis in postoperative ileus},
  url          = {http://dx.doi.org/10.1136/gutjnl-2017-313856},
  volume       = {66},
  year         = {2017},
}