ST2L Transmembrane Receptor Expression: An Immunochemical Study on Endarterectomy Samples

Background ST2 (suppression of tumorigenity) has been described as a receptor for the interleukin-33, a member of the IL-1 family of cytokines. It is associated to coronary artery disease, all-causes mortality and cardiovascular mortality. Aims The present study was designed to assess the immunohistochemical expression of the ST2 receptor (ST2L/Il-1R) in atherosclerotic plaques of formalin fixed paraffin-embedded internal carotid arteries of patients with and without cerebro-vascular symptoms. Methods and Results The study involved 41 cases (23 asymptomatic and 18 symptomatic). All the clinical and morphological parameters examined were uniformly distributed between the two groups, with a mild predominance of degree of calcification in asymptomatic cases (p = 0.01). ST2L expression was found to be more evident as a membrane pattern in macrophages when observing carotid atherosclerotic plaques of symptomatic patients, rather than in asymptomatic patients’ plaques (77.7% vs 39.1%; p = 0.015), and its expression was particularly remarkable in VI type plaque (AHA). Significantly, ST2L was marked by the endothelium of neoangiogenetic vessels on the shoulder region of the plaque, but not (apart from a few cases) in the endothelium covering the residual lumen of the vessel. Conclusions The ST2L immunohistochemical expression was for the first time investigated in a large number of human carotid atherosclerotic plaques, as for its pattern of distribution in the different plaque cell populations. Furthermore, ST2L was particularly remarkable on macrophages, as a membrane pattern, of symptomatic patients’ plaque. Considering our data, we hypothesize that ST2L/IL33 axis could drive the mechanism of plaque development and eventually rupture.

[1]  Cheuk-Man Yu,et al.  IL-33 and soluble ST2 levels as novel predictors for remission and progression of carotid plaque in early rheumatoid arthritis: A prospective study. , 2015, Seminars in arthritis and rheumatism.

[2]  Daniel Levy,et al.  The Framingham Heart Study and the epidemiology of cardiovascular disease: a historical perspective , 2014, The Lancet.

[3]  M. Iacoviello,et al.  A Novel Cardiac Bio-Marker: ST2: A Review , 2013, Molecules.

[4]  P. Quax,et al.  Soluble ST2 levels are not associated with secondary cardiovascular events and vulnerable plaque phenotype in patients with carotid artery stenosis. , 2013, Atherosclerosis.

[5]  Fan Wang,et al.  The IL-33-ST2L pathway is associated with coronary artery disease in a Chinese Han population. , 2013, American journal of human genetics.

[6]  C. Ayers,et al.  Soluble ST2 is associated with all-cause and cardiovascular mortality in a population-based cohort: the Dallas Heart Study. , 2013, Clinical chemistry.

[7]  M. Vatn,et al.  Interleukin‐33 drives a proinflammatory endothelial activation that selectively targets non‐quiescent cells , 2013, Arteriosclerosis, thrombosis, and vascular biology.

[8]  G. Keren,et al.  Interleukin-33 augments Treg cell levels: a flaw mechanism in atherosclerosis. , 2012, The Israel Medical Association journal : IMAJ.

[9]  A. Lusis Genetics of atherosclerosis. , 2012, Trends in genetics : TIG.

[10]  Enrico Ascher,et al.  Updated Society for Vascular Surgery guidelines for management of extracranial carotid disease. , 2011, Journal of vascular surgery.

[11]  G. Maurer,et al.  Interleukin-33 Induces Expression of Adhesion Molecules and Inflammatory Activation in Human Endothelial Cells and in Human Atherosclerotic Plaques , 2011, Arteriosclerosis, Thrombosis and Vascular Biology.

[12]  P. Libby,et al.  Progress and challenges in translating the biology of atherosclerosis , 2011, Nature.

[13]  Ashley M. Miller,et al.  IL-33 Reduces Macrophage Foam Cell Formation , 2010, The Journal of Immunology.

[14]  I. McInnes,et al.  Disease-associated functions of IL-33: the new kid in the IL-1 family , 2010, Nature Reviews Immunology.

[15]  S. Nakae,et al.  IL-33 and IL-33 receptors in host defense and diseases. , 2010, Allergology international : official journal of the Japanese Society of Allergology.

[16]  M. Kolácková,et al.  The counter-regulation of atherogenesis: a role for interleukin-33. , 2010, Acta medica.

[17]  M. Hayakawa,et al.  ST2 gene expression is proliferation-dependent and its ligand, IL-33, induces inflammatory reaction in endothelial cells , 2010, Molecular and Cellular Biochemistry.

[18]  I. McInnes,et al.  IL-33 Amplifies the Polarization of Alternatively Activated Macrophages That Contribute to Airway Inflammation1 , 2009, The Journal of Immunology.

[19]  Qutayba Hamid,et al.  Increased Expression of IL-33 in Severe Asthma: Evidence of Expression by Airway Smooth Muscle Cells1 , 2009, The Journal of Immunology.

[20]  E. Weinberg ST2 protein in heart disease: from discovery to mechanisms and prognostic value. , 2009, Biomarkers in medicine.

[21]  Bo-Jeong Pyun,et al.  Interleukin-33 induces angiogenesis and vascular permeability through ST2/TRAF6-mediated endothelial nitric oxide production. , 2009, Blood.

[22]  J. Pollheimer,et al.  Vascular Biology , Atherosclerosis and Endothelium Biology Nuclear Interleukin-33 Is Generally Expressed in Resting Endothelium but Rapidly Lost upon Angiogenic or Proinflammatory Activation , 2010 .

[23]  Richard T. Lee,et al.  The IL-33/ST2 pathway: therapeutic target and novel biomarker , 2008, Nature Reviews Drug Discovery.

[24]  R. Bush,et al.  Management of atherosclerotic carotid artery disease: clinical practice guidelines of the Society for Vascular Surgery. , 2008, Journal of vascular surgery.

[25]  Ashley M. Miller,et al.  IL-33 reduces the development of atherosclerosis , 2008, The Journal of experimental medicine.

[26]  D. Ribatti,et al.  Inflammatory angiogenesis in atherogenesis—a double-edged sword , 2008, Annals of medicine.

[27]  Renu Virmani,et al.  Pathology of the vulnerable plaque. , 2007, Journal of the American College of Cardiology.

[28]  Philippe Douek,et al.  The Vulnerable Carotid Artery Plaque: Current Imaging Methods and New Perspectives , 2005, Stroke.

[29]  J Fernando Bazan,et al.  IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. , 2005, Immunity.

[30]  J. Goldin,et al.  Determinants of plaque instability in atherosclerotic vascular disease. , 2005, Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology.

[31]  P. Shah,et al.  Mechanisms of plaque vulnerability and rupture. , 2003, Journal of the American College of Cardiology.

[32]  H. C. Stary,et al.  Natural history and histological classification of atherosclerotic lesions: an update. , 2000, Arteriosclerosis, thrombosis, and vascular biology.

[33]  K. Williams,et al.  Atherosclerosis--an inflammatory disease. , 1999, The New England journal of medicine.

[34]  A E Becker,et al.  Atherosclerotic plaque rupture--pathologic basis of plaque stability and instability. , 1999, Cardiovascular research.

[35]  P. Libby,et al.  The unstable atheroma. , 1997, Arteriosclerosis, thrombosis, and vascular biology.

[36]  W D Wagner,et al.  A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. , 1995, Arteriosclerosis, thrombosis, and vascular biology.