Norisoboldine, a natural AhR agonist, promotes Treg differentiation and attenuates colitis via targeting glycolysis and subsequent NAD+/SIRT1/SUV39H1/H3K9me3 signaling pathway

Abstract

Norisoboldine (NOR), a natural aryl hydrocarbon receptor (AhR) agonist, has been demonstrated to attenuate ulcerative colitis (UC) and induce the generation of Treg cells. Under UC condition, hypoxia widely exists in colonic mucosa, and secondary changes of microRNAs (miRs) expressions and glycolysis contribute to Treg differentiation. At present, we worked for exploring the deep mechanisms for NOR-promoted Treg differentiation in hypoxia and its subsequent anti-UC action from the angle of AhR/miR or AhR/glycolysis axis. Results showed that NOR promoted Treg differentiation in hypoxia and the effect was stronger relative to normoxia. It activated AhR in CD4+ T cells under hypoxic microenvironment; CH223191 (a specific AhR antagonist) and siAhR-3 abolished NOR-promoted Treg differentiation. Furthermore, the progress of glycolysis, levels of Glut1 and HK2, and expression of miR-31 rather than miR-219 and miR-490 in CD4+ T cells were downregulated by NOR treatment under hypoxic microenvironment. However, HK2 plasmid but not miR-31 mimic significantly interfered NOR-enhanced Treg polarization. In addition, NOR reduced NAD+ and SIRT1 levels, facilitated the ubiquitin-proteasomal degradation of SUV39H1 protein, and inhibited the enrichment of H3K9me3 at −1, 201 to −1,500 region of Foxp3 promoter in CD4+ T cells under hypoxic microenvironment, which was weakened by HK2 plasmid, CH223191, and siAhR-3. Finally, the correlation between NOR-mediated activation of AhR, repression of glycolysis, regulation of NAD+/SIRT1/SUV39H1/H3K9me3 signals, induction of Treg cells, and remission of colitis was confirmed in mice with DSS-induced colitis by using CH223191 and HK2 plasmid. In conclusion, NOR promoted Treg differentiation and then alleviated the development of colitis by regulating AhR/glycolysis axis and subsequent NAD+/SIRT1/SUV39H1/H3K9me3 signaling pathway.

Biologically active isoquinoline alkaloids covering 2014–2018

“…274,275 Tong et al 276 suggested that norisoboldine induced the generation of intestinal Treg cells by the activation of AhR (aryl hydrocarbon receptor) as well as promoted Treg differentiation and then reduced the development of colitis by regulating AhR/ glycolysis axis and subsequent NAD + /SIRT1/SUV39H1/H3K9me3 signaling pathway. 277 Furthermore, norisoboldine reduced IL-1β production in LPS-stimulated RAW264.7 cells and decreased the serum level of IL-1β in collagen-induced arthritis. 272,278 Finally, the compound inhibited activation of the NLRP3 inflammasome by regulating the AhR/Nrf2/ ROS signaling pathway and thereby improved the TNBS (2,4,6-trinitrobenzene sulfonic acid)-induced colitis in mice.…”

Does NLRP3 Inflammasome and Aryl Hydrocarbon Receptor Play an Interlinked Role in Bowel Inflammation and Colitis-Associated Colorectal Cancer?

“…The study further found a link between NOR and Nrf2, a nuclear transcriptional factor of Cap'n' Collar family that can inhibit NLRP3 priming [172], as the mechanism for NOR-induced inhibition of NLRP3 inflammasome activation; where NOR up-regulated the expression of Nrf2 but down-regulated the production of ROS signals in THP-1 cells [169]. Concurrently, Qi et al also demonstrated that NOR was able to produce anti-UC effects through the suppression of glycolysis and promotion of T reg cell differentiation in hypoxic microenvironments via regulation of the NAD + /SIRT1/SUV39H1/H3K9me3 signalling pathway [170].…”

“…NOR has been shown to be a natural AhR ligand by Qi et al through its up-regulation of CYP1A1 expression, promotion of AhR nuclear translocation after dissociation of the AhR/Hsp90 complex and transcriptional activity of AhR/ARNT via DNA binding to the XRE region in THP-1 cells [169]. Studies also reveal that NOR promotes T reg cell differentiation from naïve T-cells in-vitro and increased its immunosuppressive effects on T eff cells through inducing apoptotic events and inhibiting T h 1 and T h 17 differentiation [170,171]. In the context of IBD, NOR has also been demonstrated to reduce NLRP3, ASC and caspase-1 expression in TNBS-induced mice, which could imply that NOR has inhibitory effects on NLRP3 inflammasome activation through an AhR pathway [169].…”

“…AhR/STAT1-NF-κB axis Quaking inhibits NF-κB transcriptional activity and prevents NLRP3 inflammation via AhR-dependent manner [153] NAD + /SIRT1/SUV39H1/H3K9me3 axis Ameliorates colitis through promotion of T reg differentiation [170] LncRNA-PVT1-STAT3 axis Inhibits STAT3 via LncRNA-PVT1 from promoting signals for cancer inflammation [173] AhR/Nrf2/NQO1 axis AhR up-regulates Nrf2 and NQO1 levels in the colon and prevents NLRP3 inflammasome activation [175] Fibronectin/integrin β1/FAK axis Promotes cancer metastasis through ANRT down-regulation [180] While NOR and cardamonin have been described to naturally inhibit NLRP3 activation and reducing the inflammatory effects via AhR, more studies should be conducted to expand the variety of these natural inhibitors.…”

An endogenous aryl hydrocarbon receptor ligand enhances de novo generation of regulatory T cells in humans

“…Several mechanisms could explain such effect. Accordingly, Norisoboldine (NOR), an AhR agonist, has been demonstrated to enhance Treg polarization by elevating both protein and mRNA levels of Foxp3 in CD4 + T cells via a glycolysis dependent manner . Other AhR agonists such as 3,3'‐diindolylmethane (DIM) and indole‐3‐carbinol (I3C) were found to promote Treg differentiation by targeting some microRNAs (miR‐31, miR‐219, and miR‐490), which modulate Foxp3 gene expression …”