Dietary PUFAs attenuate NLRP3 inflammasome activation via enhancing macrophage autophagy

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.

Autophagy limits activation of the inflammasomes

“…147 Alternatively, chemical compounds such as rapamycin, AICAR, resveratrol, celastrol, ezetimibe, and polyunsaturated fatty acids, are known to induce autophagy. 105,[148][149][150][151][152] Although a hypocaloric diet and these compounds regulate not only autophagy but also various cellular responses, they are reported to ameliorate inflammation. [150][151][152][153][154][155] Thus, pharmacological modulation of autophagy may provide a potential therapy for inflammasome-related diseases.…”

The Influence of Dietary Fatty Acids on Immune Responses

“…Anti-inflammatory properties of DHA and EPA also include the inhibition of the NOD-like receptor protein 3 (NLRP3) inflammasome activation in macrophages [108,109]. This effect is mediated in vitro and in vivo by GPR120 and GPR40 receptors, their downstream protein β-arrestin-2 [109], and autophagy induction [110]. Interestingly, pro-inflammatory properties of SFAs (PA) are confirmed in the inflammasome-related inflammation.…”

Metabolic regulation of inflammasomes in inflammation

“…The deficiency of G‐protein‐coupled receptor 120 (GPR120) and GPR40 predominantly suppresses the influence of DHA in NLRP3 inflammasome activation, and β ‐arrestin 2, a protein downstream of GPR120, can directly interact with NLRP3 or NLRP1b but not NLRC4 or AIM2, which may explain the exclusive inhibition of NLRP3 and NLRP1b inflammasome activation . A recent study reported that ω ‐3 UFAs in dietary PUFAs alleviated NLRP3 inflammasome activation . In addition, derivatives of PUFAs generated via the lipoxygenase (LOX) and cyclooxygenase (COX) pathways may also partially influence inflammatory responses .…”

“…75 A recent study reported that x-3 UFAs in dietary PUFAs alleviated NLRP3 inflammasome activation. 76 In addition, derivatives of PUFAs generated via the lipoxygenase (LOX) and cyclooxygenase (COX) pathways may also partially influence inflammatory responses. [77][78][79] It has been shown that 15-LOX metabolites of a-linolenic acid (ALA, x-3 UFAs) inhibited NLRP3 inflammasome activation in a peroxisome proliferator-activated receptor-c (PPAR-c)-dependent manner, which in turn induced apoptosis through suppressing autophagy.…”