Abstract
Dietary PUFAs reduce atherosclerosis and macrophage inflammation, but how nucleotide-binding oligomerization domain leucine-rich repeat-containing receptor protein (NLRP3) inflammasome activation and autophagy influence PUFA-mediated atheroprotection is poorly understood. We fed Ldlr−/− mice diets containing 10% (calories) palm oil (PO) and 0.2% cholesterol, supplemented with an additional 10% of calories as PO, fish oil (FO), echium oil (EO, containing 18:4 n-3), or borage oil (BO, containing 18:3 n-6). Inflammasome activation, autophagic flux, and mitochondrial function were measured in peritoneal macrophages, blood monocytes, or liver from diet-fed mice. Compared with PO, dietary PUFAs (FO, EO, or BO) markedly inhibited inflammasome activation, shown by 1) less macrophage IL-1β secretion and caspase-1 cleavage in response to NLRP3 inflammasome activators, 2) less IL-1β secretion and caspase-1 cleavage from liver or hepatocytes in response to lipopolysaccharide (LPS), and 3) attenuated caspase-1 activity in blood monocytes. Furthermore, PUFA-enriched diets increased LC3-II expression in macrophage, aorta, and liver samples and reduced numbers of dysfunctional mitochondria in macrophages in response to LPS and palmitate, suggesting enhanced autophagic activation. Dietary PUFAs did not attenuate NLRP3 inflammasome activation in atg5-deficient macrophages, indicating that autophagic activation is critical for the PUFA-mediated inflammasome inactivation. In conclusion, dietary PUFAs reduce atherosclerosis, in part, by activation of macrophage autophagy and attenuation of NLRP3 inflammasome activation.
Highlights
Dietary PUFAs reduce atherosclerosis and macrophage inflammation, but how nucleotide-binding oligomerization domain leucine-rich repeat-containing receptor protein (NLRP3) inflammasome activation and autophagy influence PUFA-mediated atheroprotection is poorly understood
Our results suggest that dietary n-3 (FO and echium oil (EO)) and n-6 PUFAs (BO) markedly enhance activation of macrophage autophagy, improve mitochondrial function, and attenuate NLRP3 inflammasome activation, all of which partially explain their protective effects against atherosclerosis
Similar to what we found in red blood cells [23, 24], 18:3 n-3 derived from EO was sufficiently elongated-desaturated to 20:5 n-3 (EPA) and 18:3 n-6 derived from borage oil (BO) was sufficiently elongateddesaturated to 20:3 n-6 and 20:4 n-6 in thioglycollate-elicited
Summary
Dietary PUFAs reduce atherosclerosis and macrophage inflammation, but how nucleotide-binding oligomerization domain leucine-rich repeat-containing receptor protein (NLRP3) inflammasome activation and autophagy influence PUFA-mediated atheroprotection is poorly understood. Dietary PUFAs reduce atherosclerosis, in part, by activation of macrophage autophagy and attenuation of NLRP3 inflammasome activation.—Shen, L., Y. Inflammasomes can be activated by multiple types of tissue damage or by pathogen-associated molecular patterns, resulting in autocatalytic cleavage of pro-caspase-1 and processing/ maturation and secretion of the proinflammatory cytokines interleukin-1 (IL-1 ) and IL-18 Atherogenic factors such as cholesterol crystals [4, 5] can activate the nucleotide-binding oligomerization-domain leucine-rich repeat containing receptor protein (NLRP3) inflammasome in macrophages via disruption of lysosomal membranes. This article is available online at http://www.jlr.org marrow cells develop less inflammation and atherosclerosis under hypercholesterolemic conditions [4, 8], supporting the correlation between activation of the NLRP3 inflammasome in macrophages and development of atherosclerosis
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