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Imbalanced gp130 signalling in ApoE-deficient mice protects against atherosclerosis

Jones, Gareth Wyn, McLeod, Louise, Kennedy, Catherine L., Bozinovski, Steven, Najdovska, Meri and Jenkins, Brendan J. 2015. Imbalanced gp130 signalling in ApoE-deficient mice protects against atherosclerosis. Atherosclerosis 238 (2) , pp. 321-328. 10.1016/j.atherosclerosis.2014.12.037

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: Q Science > QR Microbiology > QR180 Immunology
R Medicine > R Medicine (General)
Uncontrolled Keywords: IL-6 family cytokines, Atherosclerosis, ApoE, Gp130, STAT3
Publisher: Elsevier
ISSN: 0021-9150
Funders: Arthritis Research UK
Date of Acceptance: 21 December 2014
Last Modified: 12 Jun 2019 09:43
URI: http://orca.cf.ac.uk/id/eprint/85514

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