Protection of macrophages from intracellular pathogens by miR‐182‐5p mimic—a gene expression meta‐analysis approach

Abstract

The goals of this study were to (a) define which host genes are of particular importance during the interactions between macrophages and intracellular pathogens, and (b) use this knowledge to gain fresh, experimental understanding of how macrophage activities may be manipulated during host defense. We designed an in silico method for meta-analysis of microarray gene expression data, and used this to combine data from 16 different studies of cells in the monocyte–macrophage lineage infected with seven different pathogens. Three thousand four hundred ninety-eight genes were identified, which we call the macrophage intracellular pathogen response (macIPR) gene set. As expected, the macIPR gene set showed a strong bias toward genes previously associated with the immune response. Predicted target sites for miR-182-5p (miR-182) were strongly over-represented among macIPR genes, indicating an unexpected role for miR-182-regulatable genes during intracellular pathogenesis. We therefore transfected primary human alveolar macrophage-like monocyte-derived macrophages from multiple different donors with synthetic miR-182, and found that miR-182 overexpression (a) increases proinflammatory gene induction during infection with Francisella tularensis live vaccine strain (LVS), (b) primes macrophages for increased autophagy, and (c) enhances macrophage control of both gram negative F. tularensis LVS and gram positive Bacillus anthracis ANR-1 spores. These data therefore suggest a new application for miR-182 in promoting resistance to intracellular pathogens.

SON DNA‐binding protein mediates macrophage autophagy and responses to intracellular infection

“…Macrophage genes associated with the response to intracellular pathogens were identified from three sources. We reanalysed publicly available microarray datasets, essentially as described elsewhere [32] to identify genes that were repeatedly regulated in different studies using a variety of macrophage types and intracellular pathogens. Other genes were obtained from previous RNAi or yeast two hybrid studies [33][34][35][36][37].…”

“…Infections with endospores of Bacillus anthracis ANR-1 were performed essentially as described elsewhere [32].…”

MicroRNA-183/96/182 cluster in immunity and autoimmunity

“…In addition to regulating cytokine/chemokine production in macrophages, miR-183C also regulates the phagocytosis function of macrophages. A bioinformatics analysis approach revealed that the predicted target sites of miR-182 were over-presented in a set of macrophage intracellular pathogen response (macIPR) genes ( 74 ). Further, Gregory et al.…”

The Importance of miRNA Identification During Respiratory Viral Infections

“…HMPV infection alters the expression of multiple cellular miRNAs in several cells [ 21 ]. We reported that HMPV upregulated significantly the expression of miR-182–5p, and miR-4634 in moDCs, where we highlighted the upregulation of miR-182–5p [ 15 ], which might contribute to the imbalance of Th17 cells [ 44 ] as shown in unrelated models where miR-182–5p triggers the secretion of cytokines related to a Th2-like profile, leading to high recruitment of neutrophils in the lung and secretion of cytokines such as IL-13 and IL-5 [ 16 ], and protects against different intracellular pathogens, increasing the expression of interferons and other proinflammatory cytokines [ 45 , 46 ]. In A549 cells, the miRNAs expression pattern is different.…”