Interleukin (IL)-18/IL-18 binding protein signalling modulates atherosclerotic lesion development and stability A. Corbaz, Z. Mallat, A. Scoazec, P. Graber, S. Alouani, B. Esposito,T. Humbert, P. Henry, A. Tedgui, Y. Chvatchko
Interleukin (IL)-18/IL-18 binding protein signalling modulates atherosclerotic lesion development and stability A. Corbaz, Z. Mallat, A. Scoazec, P. Graber, S. Alouani, B. Esposito,T. Humbert, P. Henry, A. Tedgui, Y. Chvatchko
Institut National de la Sant? et de la Recherche M?dicale, Unit? 541, et Institut F?d?ratif de Recherche Paris VII, H?pital Lariboisi?re, 41, Bd de la Chapelle, 75475 Paris cedex 10, France; Serono Pharmaceutical Research Institute, 1228 Plan LesOuates., Geneva, Switzerland; Service de Cardiologie, H?pital Lariboisi?re, rue Ambroise Par?, 75010 Paris, France.
Atherosclerosis is the leading cause of mortality in industrialised countries and carries an important socio economic burden. Unabated inflammatory mechanisms are responsible for changes in atherosclerotic plaque composition leading to plaque disruption and to the occurrence of acute ischemic syndromes, namely, myocardial infarction and stroke. Interleukin (IL)-18 is an inducer of IFN? with potent activities on inflammatory and vascular cells and is thought to contribute to the pathogenesis of chronic immunoinflammatory processes. We have recently detected increased production of IL-18 by macrophages and smooth muscle cells in unstable human atherosclerotic plaques that were responsible for strokes compared with stable plaques from asymptomatic patients. We now extend these findings and show increased levels of IL-18 (p < 0,05) in the circulating blood of patients with acute ischemic coronary syndromes (unstable angina and myocardial infarction, 30 males, 18 females, mean age 66,2 ± 1,8 years old, of whom 14 had unstable angina and 34 had myocardial infarction; IL-18 levels: 146,9 ± 17,1 pg ml-1) compared with nonischemic patients (10 males, 3 females, mean age 60,0 ± 5,2 years old; IL18 levels: 73,0 ± 12,2 pg ml1). Taken together, these results obtained in humans suggest a potential role for IL-18 in plaque destabilisation. An endogenous IL-18 binding protein (IL-18BP) that neutralises IL-18 has been identified. However, the role of IL-18BP in the modulation of atherogenesis and other chronic immuno inflammatory diseases in vivo is currently unknown. In this study, we show that in vivo electrotransfer of an expression plasmid DNA encoding for murine IL-18BP prevents fatty streak developmentin the thoracic aorta of apoE knockout mice (69 % reduction in lesion size, p < 0,0001) and slows progression of advanced atherosclerotic plaques in the aortic sinus (24 % reduction in lesion size, p < 0,01). More importantly, transfection with the IL-18BP plas mid induces profound changes (p < 0,001) in plaque composition (decrease in macrophage, T cell, cell death and lipid content and increase in smooth muscle cell and collagen content) leading to a stable plaque phenotype. These results identify for the first time a critical role for IL-18/IL-18BP regulation in atherosclerosis and suggest a potential role for IL-18 inhibitors in reduction of plaque development/progression and promotion of plaque stability.