title: Lysophospholipid metabolism facilitates Toll-like receptor 4 membrane translocation to regulate the inflammatory response.
abstract: Sepsis, an overwhelming inflammatory response to infection, is a major cause of morbidity and mortality worldwide and has no specific therapy. Phospholipid metabolites, such as lysophospholipids, have been shown to regulate inflammatory responses in sepsis, although their mechanism of action is not well understood. The phospholipid-metabolizing enzymes, lysophospholipid acyltransferases, control membrane phospholipid composition, function, and the inflammatory responses of innate immune cells. Here, we show that lysophosphatidylcholine acyltransferase (LPCAT) regulates inflammatory responses to LPS and other microbial stimuli. Specific inhibition of LPCAT down-regulated inflammatory cytokine production in monocytes and epithelial cells by preventing translocation of TLR4 into membrane lipid raft domains. Our observations demonstrate a new regulatory mechanism that facilitates the innate immune responses to microbial molecular patterns and provide a basis for the anti-inflammatory activity observed in many phospholipid metabolites. This provides the possibility of the development of new classes of anti-inflammatory and antisepsis agents.
authors.affiliation: Centre for Research in Biomedicine, University of the West of England, Bristol, BS16 1QY, UK. simon.jackson@uwe.ac.uk
authors.forename: Simon K
authors.initials: SK
authors.lastname: Jackson
authors.forename: Wondwossen
authors.initials: W
authors.lastname: Abate
authors.forename: Joan
authors.initials: J
authors.lastname: Parton
authors.forename: Simon
authors.initials: S
authors.lastname: Jones
authors.forename: John L
authors.initials: JL
authors.lastname: Harwood
mesh_terms: D008243:1-Acylglycerophosphocholine O-Acyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism*; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism; D009761:Nystatin / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D008246:Lysophospholipids; D011725:Pyridines; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D009761:Nystatin; D008243:1-Acylglycerophosphocholine O-Acyltransferase