Differential Induction of Isolated Lymphoid Follicles in the Gut by 18β-Glycyrrhetinic Acid

Jay M Hendricks,Diana C Lowe,Michele E Hardy,Hiroyasu Nakano

doi:10.1371/journal.pone.0100878

Jay M Hendricks, Diana C Lowe + Show 2 more

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https://doi.org/10.1371/journal.pone.0100878

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Journal: PloS one	Publication Date: Jul 3, 2014
Citations: 2	License type: CC BY 4.0

Affiliation: Washington State University, Montana State University

Abstract

18β-glycyrrhetinic acid (GRA) is a pharmacologically active component of licorice root with documented immunomodulatory properties. We reported that GRA administered orally to mice induces B cell recruitment to isolated lymphoid follicles (ILF) in the small intestine and shortens the duration of rotavirus antigen shedding. ILF are dynamic lymphoid tissues in the gut acquired post-natally upon colonization with commensal bacteria and mature through B cell recruitment to the follicles, resulting in up-regulation of IgA synthesis in response to changes in the composition of microbiota. In this study, we investigated potential mechanisms by which GRA induces ILF maturation in the ileum and the colon using mice depleted of enteric bacteria and a select group of mice genetically deficient in pattern recognition receptors. The data show GRA was unable to induce ILF maturation in ileums of mice devoid of commensal bacteria, MyD88−/− or NOD2−/− mice, but differentially induced ILF in colons. Increased expression of chemokine and chemokine receptor genes that modulate B and T cell recruitment to the mucosa were in part dependent on NOD2, TLR, and signaling adaptor protein MyD88. Together the results suggest GRA induces ILF through cooperative signals provided by bacterial ligands under normal conditions to induce B cell recruitment to ILF to the gut, but that the relative contribution of these signals differ between ileum and colon.

Highlights

We reported that glycyrrhetinic acid (GRA) administered orally induces isolated lymphoid follicles (ILF) maturation in the ileum and in addition, shortens the duration of rotavirus antigen shedding in the mouse model [12]
Colonic ILF maturation was induced by GRA in mice with normal flora (Figure 1C), and in contrast to results in the ileum, induced significant B220+ B cell recruitment to ILF in the absence of bacteria (Figure 1D)
We have explored the mechanisms by which dietary ligand GRA induces B cell recruitment to ILF

Summary

Introduction

18b-glcyrrhetinic acid (GRA) is the aglycone metabolite of glycyrrhizin, a pharmacologically active component of licorice root. Activation or inhibition of transcription factors, phosphatases, kinases and nitric oxide synthase all have been reported [5,6,7,8,9,10,11] How all of these key observations coalesce into what can be considered typical responses to GRA is important to understand, and is complicated by experiments performed in different cell lines or animal models that utilize different stimuli and routes of administration. We reported that GRA administered orally to mice induces B cell recruitment to isolated lymphoid follicles (ILF) in the gut and does so in the absence of external antigenic stimulus [12]. And consistent with a primary role of bacterial flora in ILF development in the small intestine, ILF are not present in ileums of mice deficient in intracellular pattern recognition receptor NOD1 [22]. The experiments described in the current study investigated whether GRA influences ILF maturation in the colon, and sought to understand mechanisms by which GRA induces B cell recruitment to ILF

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Results

Discussion