title: Oxidized phospholipid-induced inflammation is mediated by Toll-like receptor 2.
abstract: Oxidative tissue damage is a hallmark of many chronic inflammatory diseases. However, the precise mechanisms linking oxidative changes to inflammatory reactions remain unclear. Herein we show that Toll-like receptor 2 (TLR2) translates oxidative tissue damage into inflammatory responses by mediating the effects of oxidized phospholipids. Intraperitoneal injection of oxidized 1-palmitoyl-2-arachidonyl-sn-3-glycerophosphorylcholine (OxPAPC) resulted in upregulation of inflammatory genes in wild-type, but not in TLR2(-/-) mice. In vitro, OxPAPC induced TLR2 (but not TLR4)-dependent inflammatory gene expression and JNK and p38 signaling in macrophages. Induction of TLR2-dependent gene expression required reducible functional groups on sn-2 acyl chains of oxidized phospholipids, as well as serum cofactors. Finally, TLR2(-/-) mice were protected against carbon tetrachloride-induced oxidative tissue damage and inflammation, which was accompanied by accumulation of oxidized phospholipids in livers. Together, our findings demonstrate that TLR2 mediates cellular responses to oxidative tissue damage and they provide new insights into how oxidative stress is linked to acute and chronic inflammation.
authors.affiliation: Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Kadl
authors.forename: Poonam R
authors.initials: PR
authors.lastname: Sharma
authors.forename: Wenshu
authors.initials: W
authors.lastname: Chen
authors.forename: Rachana
authors.initials: R
authors.lastname: Agrawal
authors.forename: Akshaya K
authors.initials: AK
authors.lastname: Meher
authors.forename: Swetha
authors.initials: S
authors.lastname: Rudraiah
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Grubbs
authors.forename: Rahul
authors.initials: R
authors.lastname: Sharma
authors.forename: Norbert
authors.initials: N
authors.lastname: Leitinger
mesh_terms: D000818:Animals; D002252:Carbon Tetrachloride Poisoning / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D007150:Immunohistochemistry; D007249:Inflammation; D018950:Lipopolysaccharide Receptors / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010713:Phosphatidylcholines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics
chemical_list: D018950:Lipopolysaccharide Receptors; D010713:Phosphatidylcholines; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C472349:oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine