Leukotriene B4 enhances the generation of pro-inflammatory microRNAs to promote MyD88-dependent macrophage activation

MicroRNAs are known to control Toll like receptor activation in phagocytes. We have shown that leukotriene (LT) B 4 (LTB 4 ) positively regulates macrophage MyD88 expression by decreasing suppressor of cytokine signaling-1 (SOCS-1) mRNA stability. Here, we investigated the possibility that LTB 4 control of MyD88 expression involves the generation of microRNAs. Our data show that LTB 4 , 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. LTB 4 -mediated miR-155 generation was attributable to AP-1 activation. Furthermore, macrophage transfection with antagomirs against miR-155 and miR-146b prevented both the LTB 4 -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 WT and LT-deficient macrophages. Together, our data unveil a heretofore unrecognized role for the GPCR BLT1 in controlling expression of microRNAs which regulate MyD88-dependent activation of macrophages.