Mucosal Administration of Collagen V Ameliorates the Atherosclerotic Plaque Burden by Inducing Interleukin 35-dependent Tolerance

J Biol Chem. 2016 Feb 12;291(7):3359-70. doi: 10.1074/jbc.M115.681882. Epub 2015 Dec 31.

Abstract

We have shown previously that collagen V (col(V)) autoimmunity is a consistent feature of atherosclerosis in human coronary artery disease and in the Apoe(-/-) mouse model. We have also shown sensitization of Apoe(-/-) mice with col(V) to markedly increase the atherosclerotic burden, providing evidence of a causative role for col(V) autoimmunity in atherosclerotic pathogenesis. Here we sought to determine whether induction of immune tolerance to col(V) might ameliorate atherosclerosis, providing further evidence for a causal role for col(V) autoimmunity in atherogenesis and providing insights into the potential for immunomodulatory therapeutic interventions. Mucosal inoculation successfully induced immune tolerance to col(V) with an accompanying reduction in plaque burden in Ldlr(-/-) mice on a high-cholesterol diet. The results therefore demonstrate that inoculation with col(V) can successfully ameliorate the atherosclerotic burden, suggesting novel approaches for therapeutic interventions. Surprisingly, tolerance and reduced atherosclerotic burden were both dependent on the recently described IL-35 and not on IL-10, the immunosuppressive cytokine usually studied in the context of induced tolerance and amelioration of atherosclerotic symptoms. In addition to the above, using recombinant protein fragments, we were able to localize two epitopes of the α1(V) chain involved in col(V) autoimmunity in atherosclerotic Ldlr(-/-) mice, suggesting future courses of experimentation for the characterization of such epitopes.

Keywords: IL-35; atherosclerosis; autoimmune disease; autoimmunity; collagen type V; immunotherapy; vascular smooth muscle cells.

Publication types

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

MeSH terms

  • Administration, Intranasal
  • Animals
  • Antibodies, Neutralizing / administration & dosage
  • Antibodies, Neutralizing / metabolism
  • Atherosclerosis / etiology
  • Atherosclerosis / immunology
  • Atherosclerosis / metabolism
  • Atherosclerosis / prevention & control*
  • Autoimmunity*
  • Cattle
  • Cells, Cultured
  • Collagen Type V / administration & dosage
  • Collagen Type V / chemistry
  • Collagen Type V / genetics
  • Collagen Type V / therapeutic use*
  • Diet, Western / adverse effects
  • Epitope Mapping
  • Humans
  • Hypersensitivity, Delayed / immunology
  • Hypersensitivity, Delayed / metabolism
  • Hypersensitivity, Delayed / physiopathology
  • Hypersensitivity, Delayed / prevention & control*
  • Immune Tolerance*
  • Immunity, Mucosal
  • Interleukins / antagonists & inhibitors
  • Interleukins / metabolism*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Peptide Fragments / chemistry
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism
  • Receptors, LDL / genetics
  • Receptors, LDL / metabolism
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Spleen / immunology
  • Spleen / metabolism
  • Spleen / pathology

Substances

  • Antibodies, Neutralizing
  • COL5A1 protein, human
  • Collagen Type V
  • Interleukins
  • Peptide Fragments
  • Receptors, LDL
  • Recombinant Proteins
  • interleukin-35, mouse