title: Imbalanced gp130 signalling in ApoE-deficient mice protects against atherosclerosis.
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 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. 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.
authors.affiliation: 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.
authors.forename: Gareth W
authors.initials: GW
authors.lastname: Jones
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, MIMR-PHI Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton, Victoria, 3168, Australia.
authors.forename: Louise
authors.initials: L
authors.lastname: McLeod
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, MIMR-PHI Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton, Victoria, 3168, Australia.
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Kennedy
authors.affiliation: Lung Health Research Centre, Department of Pharmacology and Therapeutics, The University of Melbourne, Victoria, 3010, Australia.
authors.forename: Steven
authors.initials: S
authors.lastname: Bozinovski
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, MIMR-PHI Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton, Victoria, 3168, Australia.
authors.forename: Meri
authors.initials: M
authors.lastname: Najdovska
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, MIMR-PHI Institute of Medical Research, Monash University, 27-31 Wright Street, Clayton, Victoria, 3168, Australia. Electronic address: Brendan.Jenkins@monash.edu.
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Jenkins
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism* / Q000473:pathology; D001018:Aortic Diseases / Q000097:blood / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D002633:Chemotaxis; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000378:metabolism*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005260:Female; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D058226:Plaque, Atherosclerotic; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D000685:Serum Amyloid A Protein / Q000378:metabolism; D015398:Signal Transduction; D014280:Triglycerides / Q000097:blood
chemical_list: D001057:Apolipoproteins E; C494200:Il6st protein, mouse; D050796:STAT3 Transcription Factor; D000685:Serum Amyloid A Protein; C494087:Stat3 protein, mouse; D014280:Triglycerides; D050822:Cytokine Receptor gp130
keywords: ApoE; Atherosclerosis; Gp130; IL-6 family cytokines; STAT3