title: Involvement of TLR4 in oxidized LDL/β2GPI/anti-β2GPI-induced transformation of macrophages to foam cells.
abstract: OBJECTIVE
  It has been reported that oxidized low-density lipoprotein (oxLDL) forms a stable and non-dissociable complex with β2-glycoprotein I (β2GPI) and that IgG anti-β2GPI autoantibodies are able to recognize this complex, thus facilitating macrophage-derived foam cell formation in patients with antiphospholipid syndrome (APS). However, the immunopathological mechanisms of oxLDL/β2GPI complexes in promoting foam cell formation are not fully understood. In this study, we examined the role of toll-like receptor 4 (TLR4) in the oxLDL/β2GPI/anti-β2GPI complex-induced transformation of mouse peritoneal macrophages to foam cells.
  
  
  METHODS
  Oil red O staining and optical density (OD) measurements of intracellular stained oil red O solution were used to monitor the transformation of peritoneal macrophages to foam cells in TLR4-competent C3H/HeN and TLR4-mutant C3H/HeJ mice. During foam cell formation induced by the oxLDL/β2GPI/anti-β2GPI complex, the expression of TLR4 and activation of nuclear factor kappa B (NF-κB) were confirmed by analyzing the protein and mRNA levels of these compounds. Furthermore, the related active molecule expression during foam cell formation induced by the oxLDL/β2GPI/anti-β2GPI complex was examined in the presence or absence of TLR4.
  
  
  RESULTS
  The data showed that treatment with the oxLDL/β2GPI/anti-β2GPI complex markedly increased foam cell formation, the TLR4 expression, NF-κB activation, the tissue factor (TF) expression and tumor necrosis factor-α (TNF-α) and monocyte chemotactic protein-1 (MCP-1) secretion in the C3H/HeN mice. However, the transformation of macrophages to foam cells and the expression levels of phosphorylated NF-κB, TF, TNF-α and MCP-1 were significantly reduced in the C3H/HeJ mice treated with the oxLDL/β2GPI/anti-β2GPI complex. In addition, compared with that achieved by oxLDL alone, the oxLDL/β2GPI complex decreased foam cell formation and the related signaling molecule expression in the C3H/HeN mice.
  
  
  CONCLUSIONS
  Our results indicate that TLR4 plays an important role in the process of oxLDL/β2GPI/anti-β2GPI complex-induced transformation of macrophages to foam cells, which may accelerate the development of atherosclerosis in the setting of APS. However, β2GPI alone functions as an antiatherogenic protein by preventing the foam cell formation induced by oxLDL.
authors.affiliation: Department of Cardiology, Affiliated Hospital of Jiangsu University.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Zhang
authors.forename: Yachao
authors.initials: Y
authors.lastname: Xie
authors.forename: Hong
authors.initials: H
authors.lastname: Zhou
authors.forename: Ya
authors.initials: Y
authors.lastname: Xu
authors.forename: Jingjing
authors.initials: J
authors.lastname: Liu
authors.forename: Hongxiang
authors.initials: H
authors.lastname: Xie
authors.forename: Jinchuan
authors.initials: J
authors.lastname: Yan
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology*; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D005487:Foam Cells / Q000378:metabolism / Q000473:pathology*; D008077:Lipoproteins, LDL / Q000235:genetics / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D010766:Phosphorylation; D015398:Signal Transduction; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D053482:beta 2-Glycoprotein I / Q000235:genetics / Q000378:metabolism*
chemical_list: D018932:Chemokine CCL2; D008077:Lipoproteins, LDL; D016328:NF-kappa B; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D053482:beta 2-Glycoprotein I; C099252:oxidized low density lipoprotein; D013925:Thromboplastin