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, bloating, 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.

Carnosol Maintains Intestinal Barrier Function and Mucosal Immune Homeostasis in DSS-Induced Colitis

“…Since DSS-induced colitis was characterized by the of immune cell infiltration (especially innate immune cells) and proinflammatory cytokine accumulation ( 20 ), we next sought to investigate whether CA could suppress DSS-induced mucosal inflammatory responses in mice. To this end, we first looked at the number of innate cells in the lamina propria using our previously established flow cytometric gating strategy ( Figure 3A ) ( 21 ). Compared with CA-treated DSS mice, flow cytometric staining for CD45 and CD11b showed a significant increase in CD45 + CD11b + cells (total myeloid cells) in the lamina propria of DSS mice ( Figure 3B ).…”

Modulating AHR function offers exciting therapeutic potential in gut immunity and inflammation

“…Kurarinone (KAR) has a therapeutic role in irritable bowel syndrome (IBS) by modulating macrophage functions via stimulating AHR signaling. When AHR deficiency in macrophages, the effect of KAR in IBS mice was weakened [ 258 ].…”

Multi-omics for biomarker approaches in the diagnostic evaluation and management of abdominal pain and irritable bowel syndrome: what lies ahead

“…Other immune-mediated mechanisms of visceral hypersensitivity that have been described through preclinical models include changes in lamina propria macrocyte phenotype or dendritic cells, altered cytokine signaling, and T-cell activation. 65 , 71–74 …”