Immune complexes containing malondialdehyde (MDA) LDL induce apoptosis in human macrophages

Clin Immunol. 2018 Feb;187:1-9. doi: 10.1016/j.clim.2017.06.010. Epub 2017 Jul 8.

Abstract

Immune complexes (IC) containing predominantly malondialdehyde-LDL and the corresponding autoantibodies (MDA-LDL IC) predict acute cardiovascular events, while IC rich in oxidized LDL (oxLDL IC) predict cardiovascular disease progression. Our objective was to determine mechanisms that could explain these prognostic differences. We compared the effects of the interaction of oxLDL, MDA-LDL and the corresponding IC with human macrophages focusing on apoptosis, metalloproteinases, and proinflammatory cytokines. MDA-LDL IC induced higher degrees of apoptosis, higher levels of caspase-3 expression, and increased expression and release of MMP-1 and TNF compared to MDA-LDL, oxLDL, and oxLDL IC. The pro-apoptotic effects of MDA-LDL IC were inhibited by blocking TNFR 1 or FcγRI. Blocking FcγRI abrogated the induction and expression of MMPs and proinflammatory cytokines by MDA-LDL IC. In conclusion, the interaction of MDA-LDL IC with FcγRI triggers macrophage apoptosis and increased expression and release of TNF and MMP-1, which can lead to the rupture of unstable plaques.

Keywords: Apoptosis; Arteriosclerosis; Cardiovascular disease; Immune complexes; MDA-LDL; Matrix metalloproteinases; Modified LDL; Unstable atherosclerotic plaque.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigen-Antibody Complex / immunology*
  • Antigen-Antibody Complex / metabolism
  • Apoptosis / immunology*
  • Atherosclerosis / immunology*
  • Atherosclerosis / metabolism
  • Autoantibodies / immunology*
  • Autoantibodies / metabolism
  • Cardiovascular Diseases / immunology
  • Cardiovascular Diseases / metabolism
  • Caspase 3 / metabolism
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / immunology
  • Cytokines / immunology
  • Disease Progression
  • Gene Expression
  • Humans
  • Interleukin-6 / genetics
  • Interleukin-6 / immunology
  • Lipoproteins, LDL / immunology*
  • Lipoproteins, LDL / metabolism
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Malondialdehyde / analogs & derivatives*
  • Malondialdehyde / immunology
  • Malondialdehyde / metabolism
  • Matrix Metalloproteinase 1 / genetics
  • Matrix Metalloproteinase 1 / metabolism
  • Matrix Metalloproteinase 9 / genetics
  • Plaque, Atherosclerotic / immunology*
  • Plaque, Atherosclerotic / metabolism
  • Receptors, IgG / antagonists & inhibitors
  • Receptors, Tumor Necrosis Factor, Type I / antagonists & inhibitors
  • Tissue Inhibitor of Metalloproteinase-1 / genetics
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / immunology

Substances

  • Antigen-Antibody Complex
  • Autoantibodies
  • CCL2 protein, human
  • Chemokine CCL2
  • Cytokines
  • FCGR1A protein, human
  • IL6 protein, human
  • Interleukin-6
  • Lipoproteins, LDL
  • Receptors, IgG
  • Receptors, Tumor Necrosis Factor, Type I
  • TIMP1 protein, human
  • TNF protein, human
  • Tissue Inhibitor of Metalloproteinase-1
  • Tumor Necrosis Factor-alpha
  • malondialdehyde-low density lipoprotein, human
  • oxidized low density lipoprotein
  • Malondialdehyde
  • CASP3 protein, human
  • Caspase 3
  • MMP9 protein, human
  • Matrix Metalloproteinase 9
  • MMP1 protein, human
  • Matrix Metalloproteinase 1