Abstract
Antimicrobial responses play an important role in maintaining intestinal heath. Recently we reported that miR-511 may regulate TLR4 responses leading to enhanced intestinal inflammation. However, the exact mechanism remained unclear. In this study we investigated the effect of miR-511 deficiency on anti-microbial responses and DSS-induced intestinal inflammation. miR-511-deficient mice were protected from DSS-induced colitis as shown by significantly lower disease activity index, weight loss and histology scores in the miR-511-deficient group. Furthermore, reduced inflammatory cytokine responses were observed in colons of miR-511 deficient mice. In vitro studies with bone marrow-derived M2 macrophages showed reduced TLR3 and TLR4 responses in miR-511-deficient macrophages compared to WT macrophages. Subsequent RNA sequencing revealed Wdfy1 as the potential miR-511 target. WDFY1 deficiency is related to impaired TLR3/TLR4 immune responses and the expression was downregulated in miR-511-deficient macrophages and colons. Together, this study shows that miR-511 is involved in the regulation of intestinal inflammation through downstream regulation of TLR3 and TLR4 responses via Wdfy1.
Highlights
MicroRNA’s are short (18–24 nucleotides in length), endogenous, noncoding single-stranded RNA’s that regulate gene expression by controlling stability and translation of protein-coding mRNA [1]
Hundreds of other miR-511-3p potential targets are found in databases (Targetscan, Diana microT), such as Rho-associated coiled-coil containing protein kinase 2 (ROCK2), zinc finger proteins x-linked, 518B, activin A receptor type IIB (Acvr2b) and others in mice and zinc finger proteins; ROCK2 and transcription factor 4 and activating enhancer binding protein 2 beta are some targets found in humans [6], where most of the genes in mice and humans are involved in biological processes and targets such as ROCK2 and zinc finger protein 518B, and Acvr2b is conserved in both mice and humans [6]
We previously showed that CD206 deficient mice lack miR-511, which affected macrophage toll-like receptor (TLR)-4 ligation responses
Summary
MicroRNA’s (miRNAs) are short (18–24 nucleotides in length), endogenous, noncoding single-stranded RNA’s that regulate gene expression by controlling stability and translation of protein-coding mRNA [1]. MiR-511-5p is known to be degraded, and miR-511-3p is the bioactive mature strand derived from both human and mouse pre-miR-511 and the human miR-511-3p sequence is conserved in both species [6] This strand is highly conserved amongst mammalian species, and its levels correlate with CD206 expression, which is high in anti-inflammatory, wound healing, and tumor-associated macrophages [6,7,8]. We previously showed that CD206 deficient mice lack miR-511, which affected macrophage toll-like receptor (TLR)-4 ligation responses. These mice showed reduced anti-microbial responses and dampened intestinal inflammation compared to wild-type (WT) mice [16]. Our study shows downregulation of Wdfy protein in colons and bone marrow-derived macrophages in miR-511-deficient mice. This study shows that miR-511 plays an essential role in intestinal inflammation by regulating TLR3 and TLR4 responses via Wdfy in mice
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