Objective: Interleukin (IL)-6 is a key modulator of the acute phase response (APR), and while both have been implicated in atherosclerosis, the pathological role of signalling cascades downstream of IL-6 is ill-defined. Since IL-6 employs the cytokine receptor gp130 to primarily activate the STAT3 signalling cascade, 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. Finally, 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.