0383: Anti-inflammatory and anti-atherogenic effects of the inflammasome NLRP3 inhibitor, arglabin, in ApoE2Ki mice fed a high fat diet

This study was designed to evaluate the impact of inflammasome NLRP3 inhibition by the natural product, arglabin, on inflammatory response and atherosclerotic lesion in ApoE2Ki mice fed a high fat Western type diet (HFD). Arglabin was purified to homogeneity and its chemical identity was confirmed by mass spectrometry. It inhibited IL-1βand IL- 18 production in cultured C57Bl/6, Nlrp3+/+ mouse peritoneal macrophages in a concentration-dependent manner with a maximum effect at ~50 nM and EC50 values for both cytokines of ~ 10 nM. In contrast, it has no effect on both cytokines production in C57Bl/6, Nlrp3-/- cultured peritoneal macrophages. Intraperitoneal injection of arglabin (2.5 ng/g of BW, twice daily, 13 weeks) into female ApoE2Ki mice fed a HFD resulted in a decreased IL- 1βplasma level vs vehicle-treated mice (4.64 ± 1.43 pg/ml vs 11.61 ± 3.05 pg/ml, p<0.01). Surprisingly, arglabin also reduced plasma levels of total cholesterol by ~56% (p<0.01) and triglycerides by ~ 55% (p<0.05). In addition, arglabin reduced the plasma level of anti-oxLDL antibodies and oriented the pro-inflammatory M1 macrophages into the anti-inflammatory M2 phenotype in spleen and arterial lesions. Finally, marked reductions in mean lesion areas in the sinus (45 ± 19%, p<0.05) and whole aorta (60 ± 2%, p<0.01) were observed. Arglabin reduces inflammation, plasma lipids and orients tissue macrophages into an anti-inflammatory phenotype in ApoE2Ki 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.