The Flavonoid Kurarinone Regulates Macrophage Functions via Aryl Hydrocarbon Receptor and Alleviates Intestinal Inflammation in Irritable Bowel Syndrome

Xiang Xu; Qiwei Dong; Qingling Zhong; Wenbo Xiu; Qinyuan Chen; Jinxia Wang; Zhou Zhou

doi:10.2147/JIR.S329091

The Flavonoid Kurarinone Regulates Macrophage Functions via Aryl Hydrocarbon Receptor and Alleviates Intestinal Inflammation in Irritable Bowel Syndrome

J Inflamm Res. 2021 Sep 3:14:4347-4359. doi: 10.2147/JIR.S329091. eCollection 2021.

Authors

Xiang Xu^#¹, Qiwei Dong^#¹, Qingling Zhong², Wenbo Xiu^{1

2}, Qinyuan Chen^{1

2}, Jinxia Wang¹, Zhou Zhou^{1

2}

Affiliations

¹ Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, People's Republic of China.
² Department of Gastroenterology and Hepatology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, People's Republic of China.

^# Contributed equally.

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.

Keywords: aryl hydrocarbon receptor; flavonoid; irritable bowel syndrome; kurarinone; macrophage.

Grants and funding

This research was funded by Scientific Research Fund of Sichuan Provincial People’s Hospital (No. 2016LY11).