Dicer prevents activation of the type I interferon pathway in lipid-loaded macrophages

Abstract Background The expression of the endonuclease Dicer in macrophages decreases atherosclerosis and necrotic core formation by producing microRNAs such as miR-10a. This effect is associated with enhanced mitochondrial respiration lipid-loaded macrophages. However, mechanism which Dicer-dependent production miRNAs regulates function unclear. Purpose We aimed to determine on context atherosclerosis. Methods Mice a myeloid cell-specific knockout (Lys-Cre/Dicerflox/flox/Apoe−/− mice [M-Dicer−/−]) control (Lys-Cre/DicerWT/WT/Apoe−/− [M-Dicer+/+]) were fed high-fat diet (HFD) for 24 weeks. oxygen consumption rate (OCR) aortic arch plaques was studied ex vivo Seahorse Flux XF Analyzer. Bone marrow-derived (BMDMs) stimulated oxLDL (100 μg/mL) 72 h. Lipid-loaded used proteomic analysis mass spectrometry. RIP-prime- seq performed tAgo2 immunoprecipitates (IP) from Dicer+/+ Dicer−/− BMDMs. miRNA profile determined BMDMs NanoString technology. Stat1 phosphorylation Jess automated western blot system (ProteinSimple). Result OCR tissue higher than those without M-Dicer+/+ after weeks HFD feeding. decreased tissues but not (n=3–4, p<0.05). oxLDL-treated indicated that activated type I interferon signaling pathway up-regulating STAT1/2 interferon-stimulated genes, ISG15. Proteins related DNA upregulated (e.g., Dnmt3a) or downregulated Tfam) (n=5, adj.p<0.05). RIP-prime-seq showed 1376 transcripts significantly enriched tAgo IP compared (n=3–5, adj.p<0.05) including Dnmt3a Stat2. STAT1 increased Among 299 (n=6, adj.p<0.05), miR-29 miR-30 have highly conserved binding sites (predicted TargetScan) Dnmt3a. Conclusion Our results indicate limits Stat1/2-driven response due damage. may be mediated suppression miR-30. suggests targeting Dnmt3a-mediated damage therapeutic strategy limit Funding Acknowledgement Type funding sources: Public grant(s) – National budget only. Main source(s): DFG