Leukotriene B4 enhances the generation of proinflammatory microRNAs to promote MyD88-dependent macrophage activation.
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.
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202;
Zhuo
Z
Wang
Luciano Ribeiro
LR
Filgueiras
Soujuan
S
Wang
Ana Paula Moreira
AP
Serezani
Marc
M
Peters-Golden
Sonia
S
Jancar
C Henrique
CH
Serezani
D000818:Animals; D005260:Female; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007975:Leukotriene B4 / Q000235:genetics / Q000276:immunology*; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000276:immunology*; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology*; D018102:Receptors, Leukotriene B4 / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000276:immunology
D044385:GTP-Binding Protein alpha Subunits; C503704:Ltb4r1 protein, mouse; D035683:MicroRNAs; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D018102:Receptors, Leukotriene B4; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D007975:Leukotriene B4