Jones Gareth W, McLeod Louise, Kennedy Catherine L, Bozinovski Steven, Najdovska Meri, Jenkins Brendan J
Centre for Innate Immunity and Infectious Diseases, MIMR-PHI Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton, Victoria, 3168, Australia; Cardiff Institute of Infection and Immunity, The School of Medicine, Cardiff University, The Tenovus Building, Heath Campus, Cardiff, CF14 4XN, UK.
Centre for Innate Immunity and Infectious Diseases, MIMR-PHI Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton, Victoria, 3168, Australia.
Atherosclerosis. 2015 Feb;238(2):321-8. doi: 10.1016/j.atherosclerosis.2014.12.037. Epub 2014 Dec 23.
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.
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.
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.
Deregulation of gp130/STAT3 signalling augments the APR and macrophage infiltration during atherosclerosis without impacting on the development of aortic plaques.
白细胞介素（IL）-6是急性期反应（APR）的关键调节因子，虽然二者都与动脉粥样硬化有关，但特定IL-6信号级联的病理作用尚不明确。由于IL-6主要通过细胞因子受体gp130激活STAT3途径，因此我们在此评估gp130依赖的STAT3激活是否调节动脉粥样硬化。
将高脂饮食诱导的动脉粥样硬化模型建立在与gp130（F/F）基因敲入小鼠杂交的ApoE（-/-）小鼠中，这些小鼠表现出gp130依赖的STAT3激活增加以及急性期反应蛋白血清淀粉样蛋白A（SAA）的产生增加。还构建了gp130（F/F）:Stat3（-/+）:ApoE（-/-）小鼠，其STAT3激活和SAA水平经基因归一化，以及涉及ApoE（-/-）和gp130（F/F）:ApoE（-/-）小鼠的骨髓嵌合体。在高脂饮食10周后，评估主动脉粥样硬化病变，包括CD68（+）巨噬细胞的存在情况，以及血浆脂质和SAA谱。
与ApoE（-/-）同窝小鼠相比，gp130（F/F）:ApoE（-/-）小鼠的主动脉斑块形成和血浆甘油三酯水平显著降低（3倍，P<0.001）。相比之下，与ApoE（-/-）小鼠相比，gp130（F/F）:ApoE（-/-）小鼠的动脉粥样硬化斑块中CD68（+）巨噬细胞浸润增加，血浆SAA水平升高。尽管gp130（F/F）:Stat3（-/+）:ApoE（-/-）小鼠病变中的巨噬细胞数量和血浆SAA水平显著降低（P<0.05），但gp130（F/F）:ApoE（-/-）和gp130（F/F）:Stat3（-/+）:ApoE（-/-）小鼠的动脉粥样硬化病变发展和血浆甘油三酯水平相当。用gp130（F/F）:ApoE（-/-）（ApoE（F/F:ApoE））或ApoE（-/-）（ApoE（ApoE））骨髓细胞重建的ApoE（-/-）小鼠的主动脉斑块形成和血浆甘油三酯水平相当。
gp130/STAT3信号失调在动脉粥样硬化过程中增强了急性期反应和巨噬细胞浸润，但不影响主动脉斑块的发展。
