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

Abstract

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.