Abstract 176: Dietary PUFAs Enhance Macrophage Autophagy, Attenuate NLRP3 Inflammasome Activation, and Reduce Atherosclerosis

Abstract

Progression of atherosclerosis leads to progressive macrophage autophagy deficiency, which enhances inflammasome activation and atherosclerosis. We previously showed that dietary enrichment with n-3 and n-6 polyunsaturated fatty acids (PUFAs) derived from botanical oils (Echium oil (EO) containing 18:4 n-3 and borage oil (BO) containing 18:3 n-6), reduced atherosclerosis similar to that observed with fish oil (FO) consumption, compared to the saturated/monounsaturated-enriched botanical palm oil (PO). We hypothesized that dietary PUFAs enhance autophagy, which in turn, dampens macrophage NLRP3 (Nucleotide-binding oligomerization domain leucine-rich repeat containing receptor protein 3) inflammasome activation, reducing macrophage inflammation and atherosclerosis. To test the hypothesis, we fed female low density lipoprotein receptor (LDLr) knockout mice diets containing 10% (calories) PO and 0.2% cholesterol, supplemented with an additional 10% of calories as PO, EO, BO or FO for 10-16 weeks before measurement of atherosclerosis, autophagy and inflammasome activation. Compared to their PO-fed counterparts, mice fed PUFAs enriched diets (EO, BO or FO) had increased LC3-II expression in peritoneal macrophage, aorta and liver, suggesting autophagic activation. Consistent with enhanced autophagy, plasma reactive oxygen species (ROS) were significantly lower in PUFA diet-fed mice, relative to PO-fed animals. Since ROS activates, but autophagy attenuates, NLRP3 inflammasome activation, we examined whether dietary PUFAs attenuate NLRP3 inflammasome activation in mice. We found that dietary PUFAs markedly inhibited inflammasome activation, shown by: 1) less IL-1β secretion from peritoneal macrophages after ATP, oxidized LDL, or palmitate-induced NLRP3 inflammasome activation, 2) less IL-1β secretion from liver explants in response to lipopolysaccharide (LPS), and 3) deceased caspase-1 cleavage in peritoneal macrophages and liver and attenuated caspase-1 activity in blood monocytes. In conclusion, our data suggest that dietary n-3 and n-6 PUFAs are equally effective in reducing atherosclerosis, in part, by activation of macrophage autophagy and attenuation of NLRP3 inflammasome activation.