Leukotriene B4 enhances the generation of proinflammatory microRNAs to promote MyD88-dependent macrophage activation.

Wang Z, Filgueiras LR, Wang S, Serezani AP, Peters-Golden M, Jancar S, Serezani CH
J Immunol. 2014 192 (5): 2349-56

PMID: 24477912 · PMCID: PMC3943984 · DOI:10.4049/jimmunol.1302982

MicroRNAs are known to control TLR activation in phagocytes. We have shown that leukotriene (LT) B4 (LTB4) positively regulates macrophage MyD88 expression by decreasing suppressor of cytokine signaling-1 (SOCS-1) mRNA stability. In this study, we investigated the possibility that LTB4 control of MyD88 expression involves the generation of microRNAs. Our data show that LTB4, via its receptor B leukotriene receptor 1 (BLT1) and Gαi signaling, increased macrophage expression of inflammatory microRNAs, including miR-155, miR-146b, and miR-125b. LTB4-mediated miR-155 generation was attributable to activating protein-1 activation. Furthermore, macrophage transfection with antagomirs against miR-155 and miR-146b prevented both the LTB4-mediated decrease in SOCS-1 and increase in MyD88. Transfection with miR-155 and miR-146b mimics decreased SOCS-1 levels, increased MyD88 expression, and restored TLR4 responsiveness in both wild type and LT-deficient macrophages. To our knowledge, our data unveil a heretofore unrecognized role for the GPCR BLT1 in controlling expression of microRNAs that regulate MyD88-dependent activation of macrophages.

MeSH Terms (16)

Animals Female Gene Expression Regulation GTP-Binding Protein alpha Subunits Inflammation Leukotriene B4 Macrophage Activation Macrophages, Peritoneal Mice Mice, Knockout MicroRNAs Myeloid Differentiation Factor 88 Receptors, Leukotriene B4 Signal Transduction Suppressor of Cytokine Signaling 1 Protein Suppressor of Cytokine Signaling Proteins

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