gms | German Medical Science

Introduction: Postoperative ileus (POI) is a common consequence of intestinal surgery that enhances morbidity and hospitalization, but its etiology is unclear. In the present study we investigated if and how TLRs as well as IL-1-dependent pathways contribute to the onset of POI as well as the resolution.

Material and methods: POI was induced by a standardized intestinal manipulation procedure (IM) within wildtype, TLR2-, TLR4-, TLR9-, MyD88-, MyD88/TRIF-, IL1R1-, IL-18-, ASC-deficient mice. Proinflammatory gene expression and ELISA analyses were performed 3h and 24h after surgery. Neutrophil infiltration, in vitro smooth muscle contractility and gastrointestinal transit were analyzed 24h after IM. Recombinant IL-1a, IL-1b and depleting antibodies as well as IL-8 or Anakinra were administered intraperitoneally immediately after IM or preoperatively. Chimera were generated by bone marrow transplantation between wildtype and IL1R1-deficient mice. Immunohistochemistry was performed on mice and human small bowel cross sections or in mice muscularis whole mount preparations.

Results: We showed that IM led to inflammation of the muscularis externa (ME) and motility disturbances. This was dependent on MyD88- rather than TRIF or toll-like receptor (TLR)-2/4/9 signaling, indicating a crucial role for IL1R1 in POI. IL1R1-deficient mice were protected from surgery-induced POI while IL-18 deficient mice were not. Moreover, preoperative treatment of IL-1 receptor antagonist (Anakinra), or application of depleting antibodies against IL-1α and IL-1β reduced POI. Both IL1a and IL1b were secreted from ME explants following IM but their production was independent of inflammasome formation as ASC deficient mice were not protected against POI. Bone marrow chimeras demonstrated that non-hematopoietic cells mediate POI via IL1R1 signaling. Correspondingly, immunohistochemical analysis demonstrated IL1R1 expression on GFAP+ enteric glia within the myenteric plexus. Human small bowel cross-sections confirmed IL1R1 immunoreactivity within the myenteric plexus.

Conclusion: We conclude that IL1 release and glial IL1R1 activation mediates POI. Intervention with the IL-1 signaling pathway may be instrumental in treating POI.