Imbalanced gp130 signalling in ApoE-deficient mice protects against atherosclerosis

Gareth Wyn Jones, Louise McLeod, Catherine L. Kennedy, Steven Bozinovski, Meri Najdovska, Brendan J. Jenkins

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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 gp130F/F knock-in mice displaying elevated gp130-dependent STAT3 activation and production of the APR protein, serum amyloid A (SAA). Also generated were gp130F/F:Stat3?/+:ApoE?/? mice displaying genetically-normalised STAT3 activation and SAA levels, and bone marrow chimeras involving ApoE?/? and gp130F/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 gp130F/F:ApoE?/? mice were significantly reduced (3-fold, P <0.001) compared to ApoE?/? littermates. By contrast, in gp130F/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 gp130F/F:ApoE?/? and gp130F/F:Stat3?/+:ApoE?/? mice were comparable, despite a significant (P <0.05) reduction in macrophage numbers in lesions, and also plasma SAA levels, in gp130F/F:Stat3?/+:ApoE?/? mice. Aortic plaque development and plasma triglyceride levels were comparable in ApoE?/? mice reconstituted with gp130F/F:ApoE?/? (ApoEF/F:ApoE) or ApoE?/? (ApoEApoE) 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.
Original languageEnglish
Pages (from-to)321-328
Number of pages8
JournalAtherosclerosis
Volume238
Issue number2
Early online date23 Dec 2014
DOIs
Publication statusPublished - 1 Feb 2015

Keywords

  • IL-6 family cytokines
  • Atherosclerosis
  • ApoE
  • Gp130
  • STAT3

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