Anti-Inflammatory and Antiatherogenic Effects of the NLRP3 Inflammasome Inhibitor Arglabin in ApoE(2).Ki Mice Fed a High-Fat Diet

• Published in: Circulation (New York, N.Y.) N.Y.), 2015-03, Vol.131 (12), p.1061-1070
• Main Authors: Vindis, Cecile, Laffargue, Muriel, Mateo, Veronique, Buechele, Berthold, Ayala, Monica Rubio, El Gaafary, Menna, Syrovets, Tatiana, Slimane, Mohamed-Naceur, Friguet, Bertrand, Fulop, Tamas, Simmet, Thomas, El Hadri, Khadija, Rouis, Mustapha, Abderrazak, Amna, Couchie, Dominique, Mahmood, Dler Faieeq Darweesh, Elhage, Rima
• Format: Article
• Language: English
• Subjects: Cellular Biology; Life Sciences
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.114.013730

Background-This study was designed to evaluate the effect of arglabin on the NLRP3 inflammasome inhibition and atherosclerotic lesion in ApoE 2 Ki mice fed a high-fat Western-type diet. Methods and Results-Arglabin was purified, and its chemical identity was confirmed by mass spectrometry. It inhibited, in a concentration-dependent manner, interleukin (IL)-1 beta and IL-18, but not IL-6 and IL-12, production in lipopolysaccharide and cholesterol crystal-activated cultured mouse peritoneal macrophages, with a maximum effect at approximate to 50 nmol/L and EC50 values for both cytokines of approximate to 10 nmol/L. Lipopolysaccharide and cholesterol crystals did not induce IL-1 beta and IL-18 production in Nlrp3(-/-) macrophages. In addition, arglabin activated autophagy as evidenced by the increase in LC3-II protein. Intraperitoneal injection of arglabin (2.5 ng/g body weight twice daily for 13 weeks) into female ApoE(2). Ki mice fed a high-fat diet resulted in a decreased IL-1 beta plasma level compared with vehicle-treated mice (5.2 +/- 1.0 versus 11.7 +/- 1.1 pg/mL). Surprisingly, arglabin also reduced plasma levels of total cholesterol and triglycerides to 41% and 42%, respectively. Moreover, arglabin oriented the proinflammatory M1 macrophages into the anti-inflammatory M2 phenotype in spleen and arterial lesions. Finally, arglabin treatment markedly reduced the median lesion areas in the sinus and whole aorta to 54% (P=0.02) and 41% (P=0.02), respectively. Conclusions-Arglabin reduces inflammation and plasma lipids, increases autophagy, and orients tissue macrophages into an anti-inflammatory phenotype in ApoE 2. Ki mice fed a high-fat diet. Consequently, a marked reduction in atherosclerotic lesions was observed. Thus, arglabin may represent a promising new drug to treat inflammation and atherosclerosis.