Imbalanced gp130 signalling in ApoE-deficient mice protects against atherosclerosis

Atherosclerosis. 2015 Feb;238(2):321-8. doi: 10.1016/j.atherosclerosis.2014.12.037. Epub 2014 Dec 23.

Abstract

Objective: Interleukin (IL)-6 is a key modulator of the acute phase response (APR), and while both are implicated in atherosclerosis, the pathological role of specific IL-6 signalling cascades is ill-defined. Since IL-6 employs the cytokine receptor gp130 to primarily activate the STAT3 pathway, here we evaluate whether gp130-dependent STAT3 activation modulates atherosclerosis.

Methods: High-fat diet-induced atherosclerosis was established in ApoE(-/-) mice crossed with gp130(F/F) knock-in mice displaying elevated gp130-dependent STAT3 activation and production of the APR protein, serum amyloid A (SAA). Also generated were gp130(F/F):Stat3(-/+):ApoE(-/-) mice displaying genetically-normalised STAT3 activation and SAA levels, and bone marrow chimeras involving ApoE(-/-) and gp130(F/F):ApoE(-/-) mice. At 10 weeks post high-fat diet, aortic atherosclerotic lesions, including the presence of CD68(+) macrophages, and plasma lipid and SAA profiles, were assessed.

Results: Aortic plaque development and plasma triglyceride levels in gp130(F/F):ApoE(-/-) mice were significantly reduced (3-fold, P < 0.001) compared to ApoE(-/-) littermates. By contrast, in gp130(F/F):ApoE(-/-) mice, atherosclerotic plaques contained augmented CD68(+) macrophage infiltrates, and plasma SAA levels were elevated, compared to ApoE(-/-) mice. Atherosclerotic lesion development and plasma triglyceride levels in gp130(F/F):ApoE(-/-) and gp130(F/F):Stat3(-/+):ApoE(-/-) mice were comparable, despite a significant (P < 0.05) reduction in macrophage numbers in lesions, and also plasma SAA levels, in gp130(F/F):Stat3(-/+):ApoE(-/-) mice. Aortic plaque development and plasma triglyceride levels were comparable in ApoE(-/-) mice reconstituted with gp130(F/F):ApoE(-/-) (ApoE(F/F:ApoE)) or ApoE(-/-) (ApoE(ApoE)) bone marrow cells.

Conclusions: Deregulation of gp130/STAT3 signalling augments the APR and macrophage infiltration during atherosclerosis without impacting on the development of aortic plaques.

Keywords: ApoE; Atherosclerosis; Gp130; IL-6 family cytokines; STAT3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / metabolism*
  • Aorta / pathology
  • Aortic Diseases / blood
  • Aortic Diseases / genetics
  • Aortic Diseases / pathology
  • Aortic Diseases / prevention & control*
  • Apolipoproteins E / deficiency*
  • Apolipoproteins E / genetics
  • Atherosclerosis / blood
  • Atherosclerosis / genetics
  • Atherosclerosis / pathology
  • Atherosclerosis / prevention & control*
  • Chemotaxis
  • Cytokine Receptor gp130 / genetics
  • Cytokine Receptor gp130 / metabolism*
  • Diet, High-Fat
  • Disease Models, Animal
  • Female
  • Macrophages / metabolism
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation
  • Plaque, Atherosclerotic
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • Serum Amyloid A Protein / metabolism
  • Signal Transduction*
  • Triglycerides / blood

Substances

  • Apolipoproteins E
  • Il6st protein, mouse
  • STAT3 Transcription Factor
  • Serum Amyloid A Protein
  • Stat3 protein, mouse
  • Triglycerides
  • Cytokine Receptor gp130