title: Bis(monoacylglycero)phosphate inhibits TLR4-dependent RANTES production in macrophages.
abstract: Toll-like receptor 4 (TLR4) is the receptor for bacterial lipopolysaccharide (LPS) triggering production of pro-inflammatory cytokines which help eradicate the bacteria but could also be harmful when overproduced. The signaling activity of TLR4 is modulated by cholesterol level in cellular membranes, which in turn is affected by bis(monoacylglycero)phosphate (BMP), a phospholipid enriched in late endosomes. We found that exogenously added BMP isomers become incorporated into the plasma membrane and intracellular vesicles of macrophages and strongly reduced LPS-stimulated production of a chemokine RANTES, which was correlated with inhibition of interferon regulatory factor 3 (IRF3) controlling Rantes expression. To investigate the mechanism underlying the influence of BMP on TLR4 signaling we applied Laurdan and studied the impact of BMP incorporation on lipid packing, a measure for membrane order. Enrichment of model and cellular membranes with BMP significantly reduced their order and the reduction was maintained during stimulation of cells with LPS. This effect of BMP was abolished by enrichment of macrophages with cholesterol. In parallel, the inhibitory effect of BMP exerted on the TLR4-dependent phosphorylation of IRF3 was also reversed. Taken together our results indicate that BMP reduces the order of macrophage membranes which contributes to the inhibition of TLR4-dependent RANTES production.
authors.affiliation: Laboratory of Molecular Membrane Biology, Department of Cell Biology, Nencki Institute of Experimental Biology of the Polish Academy of Sciences, 3 Pasteur St., 02-093 Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Ciesielska
authors.affiliation: Laboratory for Imaging Tissue Structure and Function, Neurobiology Center, Nencki Institute of Experimental Biology of the Polish Academy of Sciences, 3 Pasteur St., 02-093 Warsaw, Poland.
authors.forename: Hanna
authors.initials: H
authors.lastname: Sas-Nowosielska
authors.affiliation: Laboratory of Molecular Membrane Biology, Department of Cell Biology, Nencki Institute of Experimental Biology of the Polish Academy of Sciences, 3 Pasteur St., 02-093 Warsaw, Poland. Electronic address: k.kwiatkowska@nencki.gov.pl.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kwiatkowska
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000096:biosynthesis*; D002784:Cholesterol / Q000378:metabolism; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008246:Lysophospholipids / Q000378:metabolism* / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D050178:Monoglycerides / Q000378:metabolism* / Q000494:pharmacology*; D000067996:RAW 264.7 Cells; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; D050838:Interferon Regulatory Factor-3; C494233:Irf3 protein, mouse; D008070:Lipopolysaccharides; D008246:Lysophospholipids; D050178:Monoglycerides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C012786:bis(monoacylglyceryl)phosphate; D002784:Cholesterol
keywords: BMP; Cholesterol; Lysobisphosphatidic acid; Membrane order; Toll-like receptors