Metformin-Inducible Small Heterodimer Partner Interacting Leucine Zipper Protein Ameliorates Intestinal Inflammation.

Seungcheon Yang,Jin-Sil Park,Hyun Sik Na,Jooyeon Jhun,Sun-Hee Hwang,Mi-La Cho,Sung-Hwan Park,Keun-Hyung Cho,Bo-In Lee,Jeongwon Choi,Seung-Jun Kim

doi:10.3389/fimmu.2021.652709

Abstract

Small heterodimer partner interacting leucine zipper protein (SMILE) is an orphan nuclear receptor and a member of the bZIP family of proteins. We investigated the mechanism by which SMILE suppressed the development of inflammatory bowel disease (IBD) using a DSS-induced colitis mouse model and peripheral blood mononuclear cells (PBMCs) from patients with ulcerative colitis (UC). Metformin, an antidiabetic drug and an inducer of AMPK, upregulated the level of SMILE in human intestinal epithelial cells and the number of SMILE-expressing cells in colon tissues from DSS-induced colitis mice compared to control mice. Overexpression of SMILE using a DNA vector reduced the severity of DSS-induced colitis and colitis-associated intestinal fibrosis compared to mock vector. Furthermore, SMILE transgenic mice showed ameliorated DSS-induced colitis compared with wild-type mice. The mRNA levels of SMILE and Foxp3 were downregulated and SMILE expression was positively correlated with Foxp3 in PBMCs from patients with UC and an inflamed mucosa. Metformin increased the levels of SMILE, AMPK, and Foxp3 but decreased the number of interleukin (IL)-17–producing T cells among PBMCs from patients with UC. These data suggest that SMILE exerts a therapeutic effect on IBD by modulating IL-17 production.

Highlights

Inflammatory bowel disease (IBD) is a chronic, progressive, and relapsing inflammatory disorder of the gastrointestinal tract related to multiple genetic and environmental factors [1]
Metformin increased the levels of Small heterodimer partner interacting leucine zipper protein (SMILE), AMPK, and Foxp3 but decreased the number of IL-17-producing T cells in peripheral blood mononuclear cells (PBMCs) from patients with ulcerative colitis (UC) and an inflamed mucosa
The mRNA level of SMILE and Foxp3 was lower and that of SMILE was positively correlated with Foxp3 in PBMCs from patients with UC with severe inflammation compared to those in remission (Figure 5B)

Summary

Introduction

Inflammatory bowel disease (IBD) is a chronic, progressive, and relapsing inflammatory disorder of the gastrointestinal tract related to multiple genetic and environmental factors [1]. The two major clinical subtypes of IBD are ulcerative colitis (UC), which features mucosal inflammation of the large intestine only, and Crohn’s disease (CD), which involves transmural chronic inflammation of Metformin-Inducible SMILE Ameliorate IBD the entire gastrointestinal tract [2]. The pathogenesis of IBD is unclear; intestinal mucosal dysfunction and uncontrolled immune responses mediated by intestinal epithelial cells and immune cells are important factors in its development [5,6,7]. Th17 cells infiltrate inflamed colonic lamina propria and disease progress is associated with an increased serum IL-17 level in colitis mice [9]. B cells secrete IL-17 in response to pathogens [13] and IL-10-producing B (B10) cells modulate the immune response during inflammation [14]

Methods

Results

Conclusion