title: Rip2 deficiency leads to increased atherosclerosis despite decreased inflammation.
abstract: BACKGROUND
  The innate immune system and in particular the pattern-recognition receptors Toll-like receptors have recently been linked to atherosclerosis. Consequently, inhibition of various signaling molecules downstream of the Toll-like receptors has been tested as a strategy to prevent progression of atherosclerosis. Receptor-interacting protein 2 (Rip2) is a serine/threonine kinase that is involved in multiple nuclear factor-κB (NFκB) activation pathways, including Toll-like receptors, and is therefore an interesting potential target for pharmaceutical intervention.
  
  
  OBJECTIVE
  We hypothesized that inhibition of Rip2 would protect against development of atherosclerosis.
  
  
  RESULTS
  Surprisingly, and contrary to our hypothesis, we found that mice transplanted with Rip2(-/-) bone marrow displayed markedly increased atherosclerotic lesions despite impaired local and systemic inflammation. Moreover, lipid uptake was increased whereas immune signaling was reduced in Rip2(-/-) macrophages. Further analysis in Rip2(-/-) macrophages showed that the lipid accumulation was scavenger-receptor independent and mediated by Toll-like receptor 4 (TLR4)-dependent lipid uptake.
  
  
  CONCLUSIONS
  Our data show that lipid accumulation and inflammation are dissociated in the vessel wall in mice with Rip2(-/-) macrophages. These results for the first time identify Rip2 as a key regulator of cellular lipid metabolism and cardiovascular disease.
authors.affiliation: Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Malin C
authors.initials: MC
authors.lastname: Levin
authors.forename: Pernilla
authors.initials: P
authors.lastname: Jirholt
authors.forename: Anna
authors.initials: A
authors.lastname: Wramstedt
authors.forename: Maria E
authors.initials: ME
authors.lastname: Johansson
authors.forename: Anna M
authors.initials: AM
authors.lastname: Lundberg
authors.forename: Maria Gustafsson
authors.initials: MG
authors.lastname: Trajkovska
authors.forename: Marcus
authors.initials: M
authors.lastname: Ståhlman
authors.forename: Per
authors.initials: P
authors.lastname: Fogelstrand
authors.forename: Mikael
authors.initials: M
authors.lastname: Brisslert
authors.forename: Linda
authors.initials: L
authors.lastname: Fogelstrand
authors.forename: Zhong-Qun
authors.initials: ZQ
authors.lastname: Yan
authors.forename: Göran K
authors.initials: GK
authors.lastname: Hansson
authors.forename: Harry
authors.initials: H
authors.lastname: Björkbacka
authors.forename: Sven-Olof
authors.initials: SO
authors.lastname: Olofsson
authors.forename: Jan
authors.initials: J
authors.lastname: Borén
mesh_terms: D000818:Animals; D053299:Apolipoprotein B-100 / Q000235:genetics; D050197:Atherosclerosis / Q000201:enzymology* / Q000209:etiology / Q000276:immunology / Q000473:pathology; D016026:Bone Marrow Transplantation; D002784:Cholesterol / Q000378:metabolism*; D006801:Humans; D007249:Inflammation; D008077:Lipoproteins, LDL / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000201:enzymology* / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010873:Pinocytosis; D012333:RNA, Messenger / Q000096:biosynthesis; D011828:Radiation Chimera; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D013047:Specific Pathogen-Free Organisms; D051197:Toll-Like Receptor 4 / Q000502:physiology; D014280:Triglycerides / Q000378:metabolism*
chemical_list: D053299:Apolipoprotein B-100; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; D011973:Receptors, LDL; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014280:Triglycerides; C032629:acetyl-LDL; D002784:Cholesterol; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506255:Ripk2 protein, mouse