Host: The Japanese Pharmacological Society, The Japanese Society of Clinical Pharmacology
Name : WCP2018 (18th World Congress of Basic and Clinical Pharmacology)
Location : Kyoto
Date : July 01, 2018 - July 06, 2018
Background: Gastrointestinal prokinetic agent, serotonin-4 receptor (5-HT4R) agonist, mosapride citrate (MOS) activates myenteric plexus neurons to release acetylcholine (ACh), which in turn induces anti-inflammatory action, but detailed pathway remains to be elucidated. Aim: Aim of this study is to clarify the anti-inflammatory mechanism of intramural plexus stimulation via 5-HT4R on leukocytes infiltration in animal model for postoperative ileus (POI). Methods: Postoperative ileus was induced by intestinal manipulation in wild type C57BL6/J (WT), 5-HT4R knock-out (S4R KO), α7nAChR knock-out (α7R KO) and M2 muscarinic AChR (M2AChR) knock-out (M2R KO) mice. Results: Intestinal manipulation induced intestinal muscularis inflammation with leukocytes infiltration, inflammatory cytokines upregulation, and motility disorder. Intramural plexus stimulation via 5-HT4R attenuated leukocytes infiltration in WT. The intramural plexus stimulation-induced anti-inflammatory action by MOS was completely suppressed in S4R KO mice, and also in chimera SR4 KO mice, which had wild type bone marrow-derived immune cells and SR4 KO body cells. On the other hand, the intramural plexus stimulation-induced anti-inflammatory action against macrophages infiltration but not neutrophils infiltration was attenuated in α7R KO mice. Selective α7nAChR agonists, PNU-282987 and AR-R17779 also inhibited only macrophages infiltration. Furthermore, α7nAChR could be detected in intestinal resident macrophages by immunohistochemistry using anti-FLAG Tag antibody in FLAG-tagged α7nAChR knocked-in mice. In contrast, the intramural plexus-mediated inhibition of neutrophils infiltration was diminished by atropine, M2AChR antagonist, methoctramine and in M2R KO mice. Conclusion: 5-HT4R stimulation inhibits leukocytes infiltration in POI possibly through intramural plexus activation. Released ACh inhibited macrophages and neutrophils infiltrations by activation of α7nAChR presumably on macrophages, and M2AChR, respectively. Thus, macrophages and neutrophils recruitment into the inflamed site is inhibited by different types of AChRs in small intestine.
