title: Macrophage beta3 integrin suppresses hyperlipidemia-induced inflammation by modulating TNFalpha expression.
abstract: OBJECTIVE
  High-fat, cholesterol-containing diets contribute to hyperlipidemia. Both high-fat diets and hyperlipidemia are associated with chronic inflammatory diseases like atherosclerosis. Integrins, heterodimeric mediators of inflammatory cell recruitment, are not generally thought to be affected by diet. However, high-fat feeding promotes inflammation, atherosclerosis, and death in hyperlipidemic mice with beta3 integrin deficiency, and treatment of humans from Western populations with oral beta3 integrin inhibitors increases mortality. The mechanisms responsible for these beta3 integrin-associated events are unknown.
  
  
  RESULTS
  Here we show that diet-induced death in beta3 integrin-deficient mice is a TNFalpha-dependent process mediated by bone marrow-derived cells. In 2 different hyperlipidemic models, apoE-null and LDL receptor-null mice, beta3-replete animals transplanted with beta3-deficient marrow died with Western-type high-fat feeding whereas beta3-deficient animals transplanted with beta3-replete marrow were rescued from diet-induced death. Transplantation with beta3-deficient marrow also increased atherosclerosis. TNFalpha [corrected] expression was increased in beta3-deficient macrophages and normalized by either retroviral or adenoviral reconstitution of beta3 integrin expression. Treatment with the anti-TNFalpha antibody infliximab rescued beta3 integrin-deficient mice from Western diet-induced death, directly implicating TNFalpha in the pathophysiology triggered by diet-induced hyperlipidemia.
  
  
  CONCLUSIONS
  These findings suggest that macrophage beta3 integrin, acting through TNFalpha, suppresses inflammation caused by hyperlipidemia attributable to high-fat feeding.
authors.affiliation: Campus Box 8127, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA.
authors.forename: Jochen G
authors.initials: JG
authors.lastname: Schneider
authors.forename: Yimin
authors.initials: Y
authors.lastname: Zhu
authors.forename: Trey
authors.initials: T
authors.lastname: Coleman
authors.forename: Clay F
authors.initials: CF
authors.lastname: Semenkovich
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D016026:Bone Marrow Transplantation; D002460:Cell Line; D002478:Cells, Cultured; D004041:Dietary Fats / Q000008:administration & dosage; D004195:Disease Models, Animal; D018450:Disease Progression; D005838:Genotype; D006801:Humans; D006949:Hyperlipidemias / Q000150:complications* / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000601:surgery; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D000069285:Infliximab; D039661:Integrin beta3 / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D001057:Apolipoproteins E; D004041:Dietary Fats; D039661:Integrin beta3; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D011973:Receptors, LDL; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab