miR-511-3p, embedded in the macrophage mannose receptor gene, contributes to intestinal inflammation

Abstract

MiR-511-3p is embedded in intron 5 of the CD206/MRC1 gene Mrc1, expressed by macrophage and dendritic cell populations. CD206 and miR-511-3p expression are co-regulated, and their contribution to intestinal inflammation is unclear. We investigated their roles in intestinal inflammation in both mouse and human systems. Colons of CD206-deficient mice displayed normal numbers of monocytes, macrophage, and dendritic cells. In experimental colitis, CD206-deficient mice had attenuated inflammation compared with wild-type (WT) mice. However, neither a CD206 antagonist nor a blocking antibody reproduced this phenotype, suggesting that CD206 was not involved in this response. Macrophages isolated from CD206-deficient mice had reduced levels of miR-511-3p and Tlr4 compared with WT, which was associated with reduced pro-inflammatory cytokine production upon lipopolysaccharides (LPS) and fecal supernatant stimulation. Macrophages overexpressing miR-511-3p showed 50% increase of Tlr4 mRNA, whereas knockdown of miR-511-3p reduced Tlr4 mRNA levels by 60%, compared with scrambled microRNA (miRNA)-transduced cells. Response to anti-tumor necrosis factor (TNF) treatment has been associated with elevated macrophage CD206 expression in the mucosa. However, in colon biopsies no statistically significant change in miR-511-3p was detected. Taken together, our data show that miR-511-3p controls macrophage-mediated microbial responses and is involved in the regulation of intestinal inflammation.

Mannose receptor modulates macrophage polarization and allergic inflammation through miR-511-3p

“…MRC1 has been suggested to play no role in disease severity of mice infected with various pathogens, including fungi and parasites. 41,42 Also, it has been shown to promote glomerulonephritis 43 in part through augmented Fc-mediated function and to enhance experimental colitis 23 through enhanced miR-511-3p–controlled activation of LPS–Toll-like receptor 4 (TLR4) signaling. Furthermore, Emara et al 4 suggested the importance of MRC1 in recognition of a major cat allergen, Fel d 1, and its subsequent influence on specific antibody response.…”

“…21,22 More recently, miR-511-3p has been found to control macrophage-mediated microbial responses and enhance intestinal inflammation. 23 …”

MicroRNAs in intestinal barrier function, inflammatory bowel disease and related cancers — their effects and therapeutic potentials

“…Patients with pediatric CD showed enhanced duodenal expression of miR-146 , miR-155 and miR-122 [13,14]. MicroRNAs regulated cytokine production in regulatory T cells of UC patients [15], miR-155 targeted Jarid2 transcripts in Th17 cells in an experimental dextran sulfate sodium (DSS)-induced colitis in mouse [16], and increased miR-511-3p expression in mouse macrophages has been linked to intestinal inflammation [17]. By contrast, miR-31 expression increased while miR-21 , miR-155 and miR-146a levels decreased in colonic CD3 + T cells in UC remission [18].…”

Lectin Receptors Expressed on Myeloid Cells

“…In fact, this upregulation has led to the MR being used as a marker for alternatively activated macrophages (304). Within the MR gene is a co-regulated microRNA (miR-511-3p), that modulates cellular activation in tumour associated and other macrophages and was recently shown to contribute to intestinal inflammation (305,306). The extracellular domain of the MR can also be cleaved by metalloproteinases following cellular activation, through Dectin-1 signalling for example, releasing a functional soluble form (sMR) (307).…”