ApoE and miR-146 in inflammation and atherosclerosis (WP3592)

Mus musculus

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.


Kristina Hanspers , Egon Willighagen , Anders Riutta , and Martina Summer-Kutmon


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Mus musculus



Pathway Ontology

disease pathway


Label Type Compact URI Comment
Lipopolysaccharide Metabolite chebi:16412
ox-LDL Metabolite chebi:60151
Nfkb2 GeneProduct ensembl:ENSMUSG00000025225
ApoE GeneProduct ensembl:ENSMUSG00000002985
p65 GeneProduct ensembl:ENSMUSG00000024927
Mir146 GeneProduct mirbase:MI0000170
PU.1 GeneProduct ncbigene:20375
Irak1 GeneProduct ensembl:ENSMUSG00000031392
Tlr4 GeneProduct ensembl:ENSMUSG00000039005
Traf6 GeneProduct ensembl:ENSMUSG00000027164
Tlr2 GeneProduct ensembl:ENSMUSG00000027995
p65 GeneProduct ensembl:ENSMUSG00000024927
Nfkb2 GeneProduct ensembl:ENSMUSG00000025225


  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