ApoE and miR-146 in inflammation and atherosclerosis (WP3926)

Homo sapiens

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]

Authors

Kristina Hanspers , Andika Tan , and Eric Weitz

Activity

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Cited In

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Organisms

Homo sapiens

Communities

Diseases ExRNA

Annotations

Disease Ontology

atherosclerosis

Cell Type Ontology

monocyte macrophage

Pathway Ontology

disease pathway disease pathway

Participants

Label Type Compact URI Comment
Lipopolysaccharide Metabolite chebi:16412
HDL Metabolite chebi:39025
ox-LDL Metabolite chebi:60151
NFKB2 GeneProduct ensembl:ENSG00000077150 Homology Mapping from Mus musculus to Homo sapiens: Original ID = En:ENSMUSG00000025225
APOE GeneProduct ensembl:ENSG00000130203 Homology Mapping from Mus musculus to Homo sapiens: Original ID = En:ENSMUSG00000002985
RELA GeneProduct ensembl:ENSG00000173039 Homology Mapping from Mus musculus to Homo sapiens: Original ID = En:ENSMUSG00000024927
MIR146A GeneProduct ensembl:ENSG00000283733 No homologues found for original id Mb:MI0000170
SPI1 GeneProduct ensembl:ENSG00000066336 Homology Mapping from Mus musculus to Homo sapiens: Original ID = L:20375
IRAK1 GeneProduct ensembl:ENSG00000184216 Homology Mapping from Mus musculus to Homo sapiens: Original ID = En:ENSMUSG00000031392
TLR4 GeneProduct ensembl:ENSG00000136869 Homology Mapping from Mus musculus to Homo sapiens: Original ID = En:ENSMUSG00000039005
TRAF6 GeneProduct ensembl:ENSG00000175104 Homology Mapping from Mus musculus to Homo sapiens: Original ID = En:ENSMUSG00000017386
TLR2 GeneProduct ensembl:ENSG00000137462 Homology Mapping from Mus musculus to Homo sapiens: Original ID = En:ENSMUSG00000027995

References

  1. Apolipoprotein E enhances microRNA-146a in monocytes and macrophages to suppress nuclear factor-κB-driven inflammation and atherosclerosis. Li K, Ching D, Luk FS, Raffai RL. Circ Res. 2015 Jun 19;117(1):e1–11. PubMed Europe PMC Scholia
  2. MicroRNA-146a & hematopoiesis: friend or foe in atherosclerosis. Raffai RL. Noncoding RNA Investig. 2018 Jul;2:43. PubMed Europe PMC Scholia