Abstract
The liver X receptors (LXR) alpha and beta are regulators of cholesterol metabolism and determinants of atherosclerosis susceptibility. Viral and bacterial pathogens have long been suspected to be modulators of atherogenesis; however, mechanisms linking innate immunity to cholesterol metabolism are poorly defined. We demonstrate here that pathogens interfere with macrophage cholesterol metabolism through inhibition of the LXR signaling pathway. Activation of Toll-like receptors (TLR) 3 and 4 by microbial ligands blocks the induction of LXR target genes including ABCA1 in cultured macrophages as well as in aortic tissue in vivo. As a consequence of these transcriptional effects, TLR3/4 ligands strongly inhibit cholesterol efflux from macrophages. Crosstalk between LXR and TLR signaling is mediated by IRF3, a specific effector of TLR3/4 that inhibits the transcriptional activity of LXR on its target promoters. These findings highlight a common mechanism whereby bacterial and viral pathogens may modulate macrophage cholesterol metabolism and cardiovascular disease.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
ATP Binding Cassette Transporter 1
-
ATP-Binding Cassette Transporters / biosynthesis
-
Adaptor Proteins, Signal Transducing
-
Animals
-
Antigens, Differentiation / genetics
-
Arteriosclerosis / metabolism
-
Arteriosclerosis / virology
-
Bacterial Infections / metabolism*
-
Cell Line
-
Cholesterol / metabolism*
-
DNA-Binding Proteins / genetics
-
Gene Expression Regulation / drug effects
-
Gene Expression Regulation / genetics
-
Genes, Regulator / genetics
-
Interferon Regulatory Factor-3
-
Ligands
-
Liver X Receptors
-
Macrophages / metabolism
-
Macrophages / virology
-
Membrane Glycoproteins / drug effects
-
Membrane Glycoproteins / metabolism*
-
Mice
-
Mice, Inbred C57BL
-
Mice, Knockout
-
Myeloid Differentiation Factor 88
-
NF-kappa B / genetics
-
Orphan Nuclear Receptors
-
Promoter Regions, Genetic / drug effects
-
Promoter Regions, Genetic / genetics
-
Receptors, Cell Surface / drug effects
-
Receptors, Cell Surface / metabolism*
-
Receptors, Cytoplasmic and Nuclear / metabolism*
-
Receptors, Immunologic / genetics
-
Signal Transduction / physiology
-
Toll-Like Receptor 3
-
Toll-Like Receptors
-
Transcription Factors / genetics
-
Virus Diseases / metabolism*
Substances
-
ATP Binding Cassette Transporter 1
-
ATP-Binding Cassette Transporters
-
Adaptor Proteins, Signal Transducing
-
Antigens, Differentiation
-
DNA-Binding Proteins
-
Interferon Regulatory Factor-3
-
Irf3 protein, mouse
-
Ligands
-
Liver X Receptors
-
Membrane Glycoproteins
-
Myd88 protein, mouse
-
Myeloid Differentiation Factor 88
-
NF-kappa B
-
Nr1h3 protein, mouse
-
Orphan Nuclear Receptors
-
Receptors, Cell Surface
-
Receptors, Cytoplasmic and Nuclear
-
Receptors, Immunologic
-
Toll-Like Receptor 3
-
Toll-Like Receptors
-
Transcription Factors
-
Cholesterol