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 and Andika Tan

Cited In

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Organism

Homo sapiens

Communities

Diseases

Annotations

Pathway Ontology: disease pathway

Disease Ontology: atherosclerosis

Participants

Label	Type	Compact Identifier
Lipopolysaccharide	Metabolite	chebi:16412
HDL	Metabolite	chebi:39025
ox-LDL	Metabolite	chebi:60151
HDL	Metabolite	chebi:39025
NFKB2	GeneProduct	ensembl:ENSG00000077150
APOE	GeneProduct	ensembl:ENSG00000130203
RELA	GeneProduct	ensembl:ENSG00000173039
MIR146A	GeneProduct	ensembl:ENSG00000283733
SPI1	GeneProduct	ensembl:ENSG00000066336
IRAK1	GeneProduct	ensembl:ENSG00000184216
TLR4	GeneProduct	ensembl:ENSG00000136869
TRAF6	GeneProduct	ensembl:ENSG00000175104
TLR2	GeneProduct	ensembl:ENSG00000137462
RELA	GeneProduct	ensembl:ENSG00000173039
NFKB2	GeneProduct	ensembl:ENSG00000077150

References

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