The flavonoid kurarinone regulates macrophage functions via aryl hydrocarbon receptor and alleviates intestinal inflammation in irritable bowel syndrome

Abstract

Background: Irritable bowel syndrome (IBS) is characterized with abdominal pain, bloat-ing, and changes in bowel habits, and dealing with IBS is still a clinical challenge. The pathogenesis of IBS has been reported to be linked to low-grade mucosal inflammation, and macrophages contribute to the pathological process of this disease. Kurarinone (KAR), a flavanoid derived from Sophora flavescens, has been found medically effective in many inflammatory conditions and cancers. KAR was previously reported to inhibit LPS-induced expression of inflammatory cytokines in macrophages, whether and how KAR regulates the functions of macrophage in IBS remains to be elusive. Methods: We established a TNBS-induced IBS mouse model, in which KAR was administrated, and mucosal cytokine expression was measured by qRT-PCR. Additionally, mouse macrophages were generated in vitro and their responses to LPS were evaluated by flow cytometry and qRT-PCR. AhR+/+ or AhR−/- macrophages were transferred into DTx-treated CD11b-DTR transgenic mice to investigate the role of AhR in IBS. We collected colonic biopsies and peripheral blood samples from 64 patients with IBS, and analyzed AhR expression by qRT-PCR. Results: We found KAR effectively alleviated visceral hypersensitivity and maintained intestinal barrier functions in mice with IBS. KAR inhibited LPS-induced macrophage activation and expression of pro-inflammatory genes, while increased anti-inflammatory gene expression including IL-10 in an AhR-dependent manner. Using macrophage-depleted mice, we found that chimera mice with AhR−/- macrophages were more susceptible to TNBS-induced IBS and the therapeutic effect of KAR on IBS was significantly impaired in mice with AhR−/- macrophages. Additionally, we found AhR expression in macrophages of IBS patients was associated with the disease severity. Conclusion: Our findings provide new evidences that KAR regulates IBS development via macrophage-intrinsic AhR. KAR might show promise as an immunomodulatory therapeutic agent in treating IBS.