Abstract
Regulation of miR-146a abundance and its role in intestinal inflammation and particularly in intestinal epithelial cells (IECs) has been poorly studied. Here we study the relationship between bacterial antigens and inflammatory stimuli, and miR-146a expression using IEC lines and models of colitis (trinitrobenzenesulfonic acid (TNBS), dextran sulfate sodium (DSS) and the CD4 + CD62L + T cell transfer model). Specific bacterial antigens and cytokines (LPS, flagelin and IL-1β/TNF) stimulate miR-146a expression, while peptidoglycan, muramyldipeptide and CpG DNA have no effect. Overexpression of miR-146a by LPS depends on the activation of the TLR4/MyD88/NF-kB and Akt pathways. Accordingly, the induction of miR-146a is lower in TLR4, but not in TLR2 knock out mice in both basal and colitic conditions. miR-146a overexpression in IECs induces immune tolerance, inhibiting cytokine production (MCP-1 and GROα/IL-8) in response to LPS (IEC18) or IL-1β (Caco-2). Intestinal inflammation induced by chemical damage to the epithelium (DSS and TNBS models) induces miR-146a, but no effect is observed in the lymphocyte transfer model. Finally, we found that miR-146a expression is upregulated in purified IECs from villi vs. crypts. Our results indicate that miR-146a is a key molecule in the interaction among IECs, inflammatory stimuli and the microbiota.
Highlights
Intestinal homeostasis depends on the interaction between bacteria and the intestinal epithelium
Because miR-146a is expressed in hematopoietic cells, and these cells are key mediators of the immune response, most studies have been restricted to these cell types and the role of miR-146a in the immune response mediated by Intestinal epithelial cells (IECs) has been poorly studied
Quiescent IEC18 cells displayed low expression of mature miR-146a, which shifted to substantially increased levels after stimulation with LPS, flagellin, TNF or IL-1β (Fig. 1b)
Summary
Intestinal homeostasis depends on the interaction between bacteria and the intestinal epithelium. In this study we aimed to better understand the regulation of miR-146a in intestinal inflammation studying its expression in three animal models of colitis, which differ in the involvement of the intestinal mucosal barrier and, in the level of contact with the intestinal microbiota. Our second objective in this study aims to further report the role of miR-146a in intestinal inflammation and the maintenance of immune tolerance by IECs. We studied the effect of bacterial antigens and cytokines on the expression of miR-146a using IEC lines, and overexpressed miR-146a in IECs to explore the hypothesis that it may contribute to prevent overstimulation of the immune response. Characterization of the function of miR-146a in intestinal inflammation and tolerance will contribute to better understand these processes and their contribution to the pathogenesis of inflammatory diseases like inflammatory bowel disease and even of systemic diseases in which a role for the intestinal microbiota has been suggested
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