Critical Role of Alternative M2 Skewing in miR-155 Deletion-Mediated Protection of Colitis.

Jintao Li,Hongxia Guo,Weiping Fan,Ji Zhang,Shimin Yang,Yuzhang Wu,Xue Luo,Hongli Li,Zigang Shen,Ping Yan,Nan Ye,Haiyang He,Tiantian Yu,Hui Lin,Zhiqiang Tian,Guoping Ai

doi:10.3389/fimmu.2018.00904

Jintao Li, Hongxia Guo + Show 14 more

Open Access

https://doi.org/10.3389/fimmu.2018.00904

Copy DOI

Abstract

Inflammatory bowel disease (IBD) is associated with dysregulation of both innate and adaptive immune response in the intestine. MicroRNA (miR)-155 is frequently expressed and functions in many immune cell types. Besides its function in adaptive immunity, miR-155 is a key regulator of the innate immune response in macrophages, dendritic cells, and even in epithelia cells. Although the roles of miR-155 within T and B lymphocytes in colitis have been reported, its function in innate immune cells has not been thoroughly examined. In this study, the dextran sulfate sodium (DSS)-induced colitis model was established in wild-type (WT) and miR-155−/− mice. Our results showed that miR-155 deficiency in macrophages recapitulated the alleviated colitis feature of miR-155−/− mice and appeared to skew toward the alterative M2 phenotype. Notably, the predominance of M2 in colon can result in dampened intestinal immune cell proliferation and inhibit CD4 T cell polarization toward Th1 and Th17. Moreover, C/EBPβ and SOCS1 were demonstrated as two key functional targets in this process. We also provided evidence for use of miR-155 inhibitor to treat colitis. Collectively, the findings highlight the central role of alternative M2 skewing for miR-155 function in colitis and reveal that macrophages might be a main target for therapeutics.

Highlights

The intestine maintains an elaborate balance between immune responses and immune tolerance to microbiota, which depends upon diverse regulatory mechanisms
In the murine colitis model induced by dextran sulfate sodium (DSS), which mimics the hallmarks of Inflammatory bowel disease (IBD) in human patients, DSS administration leads to increased intestinal permeability and subsequent invasion of intestinal microflora through epithelial cell damage
Diverse regulatory mechanisms cooperate to maintain intestinal homeostasis, and breakdown in the intestinal epithelium or host immune system might lead to the pathology of colitis [40]

Summary

Introduction

The intestine maintains an elaborate balance between immune responses and immune tolerance to microbiota, which depends upon diverse regulatory mechanisms. Inflammatory bowel diseases (IBDs), including ulcerative colitis (UC) and Crohn’s disease, are characterized by dysregulated intestinal immune response. The immune cells of the gut mucosa involved in IBD pathogenesis include the innate arm dendritic cells (DCs), macrophages, innate lymphoid cells (ILCs), and neutrophils, and the adaptive arm Foxp3+ regulatory T (Treg) cells, interferon-γ-producing type 1 helper T cells (Th1) and interleukin (IL)-17-producing helper T cells (Th17 cells) [1]. Intestinal epithelial cells (IECs), which sense intestinal contents through surface receptors and secrete regulatory factors, are involved as well [2]. In the murine colitis model induced by dextran sulfate sodium (DSS), which mimics the hallmarks of IBD in human patients, DSS administration leads to increased intestinal permeability and subsequent invasion of intestinal microflora through epithelial cell damage. DCs and macrophages accumulate rapidly in colon (from 5 to 12 days), while T and B cells infiltrate during the late phase (from 8 to 25 days) [3]

Methods

Results

Conclusion