Imbalanced gp130 signalling in ApoE-deficient mice protects against atherosclerosis

- Deregulated gp130 activation in gp130F/F:ApoE−/− mice suppresses atherosclerosis.
- Modulation of aortic plaque formation by gp130 is independent of STAT3 signalling.
- Gp130/STAT3 signalling promotes plaque macrophage infiltrates and SAA production.
- Gp130 signalling in bone marrow cells does not contribute to atherosclerosis.

ObjectiveInterleukin (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.MethodsHigh-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.ResultsAortic 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.ConclusionsDeregulation of gp130/STAT3 signalling augments the APR and macrophage infiltration during atherosclerosis without impacting on the development of aortic plaques.