Apolipoprotein E (ApoE) enhances purine-rich PU-box-binding protein 1 (PU.1)-dependent miR-146a transcription to suppress nuclear factor-κB (NF-κB)-driven monocyte and macrophage activation and thereby inflammation and atherosclerosis.
Environmental ligands of toll-like receptors (TLRs), including lipopolysaccharide (LPS) and oxidized low-density lipoprotein (oxLDL), caused by hyperlipidemia provoke inflammatory signaling in monocytes and macrophages resulting in NF-κB activation. Gene transcription from NF-κB activity results in the production of inflammatory mediators, including proatherogenic cytokines. It also results in the production of primary miR-146a (pri-miR-146a) that is subsequently processed into mature miR-146a that silences the expression of key TLR-adaptor molecules interleukin-1 receptor-associated kinase 1 (IRAK1) and TNF receptor-associated factor 6 (TRAF6). The production of miR-146a thereby serves as a regulatory feedback loop to suppress NF-κB activity and resolve inflammation. Findings from our study identified that cellular apoE expression contributes to amplify this regulatory feedback loop by increasing PU.1-dependent transcription of pri-miR-146a and thereby mature miR-146a production.
Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP3926 CPTAC Assay Portal]This pathway was inferred from Mus musculus pathway "ApoE and miR-146 in inflammation and atherosclerosis", WP3592 revision 89801, with a 90.0% conversion rate.d6bHomology Mapping from Mus musculus to Homo sapiens: Original ID = En:ENSMUSG00000025225Homology Mapping from Mus musculus to Homo sapiens: Original ID = En:ENSMUSG00000002985Homology Mapping from Mus musculus to Homo sapiens: Original ID = En:ENSMUSG00000024927No homologues found for original id Mb:MI0000170Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:20375Homology Mapping from Mus musculus to Homo sapiens: Original ID = En:ENSMUSG00000031392Homology Mapping from Mus musculus to Homo sapiens: Original ID = En:ENSMUSG00000039005Homology Mapping from Mus musculus to Homo sapiens: Original ID = En:ENSMUSG00000017386Homology Mapping from Mus musculus to Homo sapiens: Original ID = En:ENSMUSG00000027995Homology Mapping from Mus musculus to Homo sapiens: Original ID = En:ENSMUSG00000024927Homology Mapping from Mus musculus to Homo sapiens: Original ID = En:ENSMUSG00000025225ceedisease pathwayPW:0000013Pathway OntologyatherosclerosisDOID:1936Human Disease Ontology25904598PubMedApolipoprotein E enhances microRNA-146a in monocytes and macrophages to suppress nuclear factor-κB-driven inflammation and atherosclerosis.Circ Res2015Li KChing DLuk FSRaffai RL30101215PubMedMicroRNA-146a& hematopoiesis: friend or foe in atherosclerosis.Noncoding RNA Investig2018Raffai RL