Crosstalk between LXR and toll-like receptor signaling mediates bacterial and viral antagonism of cholesterol metabolism.
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.
Castrillo
Antonio
A
Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Joseph
Sean B
SB
Vaidya
Sagar A
SA
Haberland
Margaret
M
Fogelman
Alan M
AM
Cheng
Genhong
G
Tontonoz
Peter
P
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics; D001161:Arteriosclerosis / Q000378:metabolism / Q000821:virology; D001424:Bacterial Infections / Q000378:metabolism*; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005809:Genes, Regulator / Q000235:genetics; D050838:Interferon Regulatory Factor-3; D008024:Ligands; D000071518:Liver X Receptors; D008264:Macrophages / Q000378:metabolism / Q000821:virology; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B / Q000235:genetics; D057093:Orphan Nuclear Receptors; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D014157:Transcription Factors / Q000235:genetics; D014777:Virus Diseases / Q000378:metabolism*
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D004268:DNA-Binding Proteins; D050838:Interferon Regulatory Factor-3; C494233:Irf3 protein, mouse; D008024:Ligands; D000071518:Liver X Receptors; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D011971:Receptors, Immunologic; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D014157:Transcription Factors; D002784:Cholesterol