miR-146a regulates the crosstalk between intestinal epithelial cells, microbial components and inflammatory stimuli

• Published in: Scientific reports 2018-11, Vol.8 (1), p.17350-12, Article 17350
• Main Authors: Anzola, Andrea, González, Raquel, Gámez-Belmonte, Reyes, Ocón, Borja, Aranda, Carlos J., Martínez-Moya, Patricia, López-Posadas, Rocío, Hernández-Chirlaque, Cristina, Sánchez de Medina, Fermín, Martínez-Augustin, Olga
• Format: Article
• Language: English
• Subjects: 13; 14; 38/109; 38/77; 38/89; 38/90; 631/250/256/2515; 631/250/262/2106/2108; 631/337/505; 64; 64/110; 64/60; 96; AKT protein; Animal models; Animals; Antigens; CD4 antigen; Cell Line; Colitis; Colitis - chemically induced; Colitis - genetics; Colitis - immunology; Colitis - pathology; Colon; CpG islands; Dextran; Dextran sulfate; Epithelial cells; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelium; Female; Flagellin - toxicity; Gastrointestinal Microbiome - genetics; Homeodomain Proteins - genetics; Humanities and Social Sciences; Humans; Immunological tolerance; Inflammation; Interleukin 8; Intestine; Intestines - cytology; Intestines - microbiology; L-selectin; Lipopolysaccharides; Lipopolysaccharides - toxicity; Lymphocytes; Lymphocytes T; Mice, Inbred C57BL; Mice, Knockout; MicroRNAs - genetics; MicroRNAs - metabolism; Monocyte chemoattractant protein 1; multidisciplinary; MyD88 protein; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - metabolism; NF-κB protein; Peptidoglycans; Rats, Wistar; Rodents; Science; Science (multidisciplinary); Sodium; TLR2 protein; TLR4 protein; Toll-Like Receptor 2 - genetics; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - metabolism; Toll-like receptors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-35338-y

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.