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

<jats:sec> <jats:title>Background—</jats:title> <jats:p> This study was designed to evaluate the effect of arglabin on the NLRP3 inflammasome inhibition and atherosclerotic lesion in ApoE <jats:sub>2</jats:sub> Ki mice fed a high-fat Western-type diet. </jats:p> </jats:sec> <jats:sec> <jats:title>Methods and Results—</jats:title> <jats:p> Arglabin was purified, and its chemical identity was confirmed by mass spectrometry. It inhibited, in a concentration-dependent manner, interleukin (IL)-1β 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 ≈50 nmol/L and EC <jats:sub>50</jats:sub> values for both cytokines of ≈ 10 nmol/L. Lipopolysaccharide and cholesterol crystals did not induce IL-1β and IL-18 production in Nlrp3 <jats:sup>−/−</jats:sup> 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 <jats:sub>2</jats:sub> .Ki mice fed a high-fat diet resulted in a decreased IL-1β 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% ( <jats:italic>P</jats:italic> =0.02) and 41% ( <jats:italic>P</jats:italic> =0.02), respectively. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions—</jats:title> <jats:p> Arglabin reduces inflammation and plasma lipids, increases autophagy, and orients tissue macrophages into an anti-inflammatory phenotype in ApoE <jats:sub>2</jats:sub> .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. </jats:p> </jats:sec>