Postoperative ileus involves interleukin-1 receptor signaling in enteric glia.
OBJECTIVE
Postoperative ileus (POI) is a common consequence of abdominal surgery that increases the risk of postoperative complications and morbidity. We investigated the cellular mechanisms and immune responses involved in the pathogenesis of POI.


METHODS
We studied a mouse model of POI in which intestinal manipulation leads to inflammation of the muscularis externa and disrupts motility. We used C57BL/6 (control) mice as well as mice deficient in Toll-like receptors (TLRs) and cytokine signaling components (TLR-2(-/-), TLR-4(-/-), TLR-2/4(-/-), MyD88(-/-), MyD88/TLR adaptor molecule 1(-/-), interleukin-1 receptor [IL-1R1](-/-), and interleukin (IL)-18(-/-) mice). Bone marrow transplantation experiments were performed to determine which cytokine receptors and cell types are involved in the pathogenesis of POI.


RESULTS
Development of POI did not require TLRs 2, 4, or 9 or MyD88/TLR adaptor molecule 2 but did require MyD88, indicating a role for IL-1R1. IL-1R1(-/-) mice did not develop POI; however, mice deficient in IL-18, which also signals via MyD88, developed POI. Mice given injections of an IL-1 receptor antagonist (anakinra) or antibodies to deplete IL-1α and IL-1β before intestinal manipulation were protected from POI. Induction of POI activated the inflammasome in muscularis externa tissues of C57BL6 mice, and IL-1α and IL-1β were released in ex vivo organ bath cultures. In bone marrow transplantation experiments, the development of POI required activation of IL-1 receptor in nonhematopoietic cells. IL-1R1 was expressed by enteric glial cells in the myenteric plexus layer, and cultured primary enteric glia cells expressed IL-6 and the chemokine monocyte chemotactic protein 1 in response to IL-1β stimulation. Immunohistochemical analysis of human small bowel tissue samples confirmed expression of IL-1R1 in the ganglia of the myenteric plexus.


CONCLUSIONS
IL-1 signaling, via IL-1R1 and MyD88, is required for development of POI after intestinal manipulation in mice. Agents that interfere with the IL-1 signaling pathway are likely to be effective in the treatment of POI.
Department of Surgery, University of Bonn, Bonn, Germany.
Burkhard
B
Stoffels
Department of Surgery, University of Bonn, Bonn, Germany.
Kristof Johannes
KJ
Hupa
Tytgat Institute of Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.
Susanne A
SA
Snoek
Tytgat Institute of Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.
Sjoerd
S
van Bree
Department of Surgery, University of Bonn, Bonn, Germany.
Kathy
K
Stein
Department of Surgery, University of Bonn, Bonn, Germany.
Timo
T
Schwandt
Department of Surgery, University of Bonn, Bonn, Germany.
Tim O
TO
Vilz
Department of Surgery, University of Bonn, Bonn, Germany.
Mariola
M
Lysson
Center for Experimental Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
Cornelis Van't
CV
Veer
Department of Neurology, Clinical Neuroscience Unit, University of Bonn, Bonn, Germany.
Markus P
MP
Kummer
Institute for Clinical Chemistry and Pharmacology, University of Bonn, Bonn, Germany.
Veit
V
Hornung
Department of Surgery, University of Bonn, Bonn, Germany.
Joerg C
JC
Kalff
Tytgat Institute of Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands. Electronic address: w.j.dejonge@amc.nl.
Wouter J
WJ
de Jonge
Department of Surgery, University of Bonn, Bonn, Germany. Electronic address: sven.wehner@ukb.uni-bonn.de.
Sven
S
Wehner
D000818:Animals; D004195:Disease Models, Animal; D005769:Gastrointestinal Motility / Q000276:immunology*; D045823:Ileus / Q000276:immunology* / Q000378:metabolism; D007375:Interleukin-1 / Q000276:immunology* / Q000378:metabolism; D020382:Interleukin-18 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009130:Muscle, Smooth / Q000276:immunology* / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D009197:Myenteric Plexus / Q000276:immunology* / Q000378:metabolism; D009457:Neuroglia / Q000276:immunology* / Q000378:metabolism; D011183:Postoperative Complications / Q000276:immunology* / Q000378:metabolism; D053573:Receptors, Interleukin-1 Type I / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology / Q000378:metabolism
C583355:IL1R1 protein, mouse; D007375:Interleukin-1; D020382:Interleukin-18; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D053573:Receptors, Interleukin-1 Type I; D051193:Toll-Like Receptors
GFAP; GI; Gastrointestinal Dysmotility; IL; IL-1 receptor antagonist; IL-18R; IL-1R; IL-1R1; IL-1ra; IM; Ig; Inflammatory Response; Innate Immunity; MCP-1; ME; MPO; POI; Pathogen Recognition; TLR; Toll-like receptor; WT; gastrointestinal; glial fibrillary acidic protein; immunoglobulin; interleukin; interleukin 1 receptor; interleukin-1 receptor type I; interleukin-18 receptor; intestinal manipulation; mRNA; messenger RNA; monocyte chemotactic protein 1; muscularis externa; myeloperoxidase; postoperative ileus; wild-type