Anti-Inflammatory and Anti-Atherogenic Effects of the Inflammasome NLRP3 Inhibitor, Arglabin, in ApoE2.Ki Mice Fed a High Fat Diet

Background —This study was designed to evaluate the effect of arglabin on inflammasome NLRP3 inhibition and atherosclerotic lesion in ApoE2Ki mice fed a high fat Western-type diet (HFD). Methods and Results —Arglabin was purified and its chemical identity was confirmed by mass spectrometry. It inhibited, in a concentration-dependent manner, IL-1β and IL-18 production, but not IL-6 and IL-12, in LPS and cholesterol crystal-activated cultured mouse peritoneal macrophages with a maximum effect at ~50 nM and EC 50 values for both cytokines of ~ 10 nM. LPS and cholesterol crystals did not induce IL-1β and IL-18 production in Nlrp3 -/- macrophages. In addition, arglabin activated autophagy as evidenced by the increase of LC3-II protein. Intraperitoneal injection of arglabin (2.5 ng/g of bw, twice daily, 13 weeks) into female ApoE 2 .Ki mice fed a HFD resulted in a decreased IL-1β plasma level vs vehicle-treated mice (5.2 ± 1.0 pg/mL vs 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, plasma lipids, increases autophagy, and orients tissue macrophages into an anti-inflammatory phenotype in ApoE 2 .Ki mice fed a HFD. Consequently, a marked reduction of atherosclerotic lesions was observed. Thus, arglabin may represent a new promising drug to treat inflammation and atherosclerosis.