Lipid regulation of NLRP3 inflammasome activity through organelle stress

Multiple classes of endogenous lipids, including oxidized low-density lipoprotein (LDL), saturated fatty acids, and sphingolipids, activate the mammalian NLRP3 inflammasome and can contribute to the progression of certain inflammatory diseases. Lipid activators of NLRP3 often share common features, such as slow-onset kinetics and the ability to provide both priming and triggering signals for inflammasome activation. Organelle stress, especially at mitochondria, lysosomes, and the endoplasmic reticulum, is required for lipid activation of NLRP3, while attenuation of organelle stress by certain lipids can inhibit NLRP3 activity. Inflammation driven by the NLRP3 inflammasome in macrophages is an important contributor to chronic metabolic diseases that affect growing numbers of individuals. Many of these diseases involve the pathologic accumulation of endogenous lipids or their oxidation products, which can activate NLRP3. Other endogenous lipids, however, can inhibit the activation of NLRP3. The intracellular mechanisms by which these lipids modulate NLRP3 activity are now being identified. This review discusses emerging evidence suggesting that organelle stress, particularly involving mitochondria, lysosomes, and the endoplasmic reticulum, may be key in lipid-induced modification of NLRP3 inflammasome activity. Inflammation driven by the NLRP3 inflammasome in macrophages is an important contributor to chronic metabolic diseases that affect growing numbers of individuals. Many of these diseases involve the pathologic accumulation of endogenous lipids or their oxidation products, which can activate NLRP3. Other endogenous lipids, however, can inhibit the activation of NLRP3. The intracellular mechanisms by which these lipids modulate NLRP3 activity are now being identified. This review discusses emerging evidence suggesting that organelle stress, particularly involving mitochondria, lysosomes, and the endoplasmic reticulum, may be key in lipid-induced modification of NLRP3 inflammasome activity. process by which cell contents, including organelles, are engulfed in an autophagosomal membrane and transported to lysosomes for degradation and recycling. steroid lipids synthesized in the liver that play a key role in gastrointestinal absorption of lipids and lipid-soluble vitamins. group of proteases that mature in lysosomes. Mature cathepsins are found intracellularly and extracellularly and have a diverse substrate range. macrophages that have accumulated large quantities of lipids in intracellular lipid droplets, giving them a foamy appearance. Foam cells are common in certain diseases, including atherosclerosis. macromolecular complex that initiates cell death and cytokine secretion in response to pathogen or danger signals. Canonical inflammasomes consist of a sensor protein (NLRP1, NLRP3, NLRC4, AIM2, or pyrin), the adaptor protein ASC, and caspase-1. type of tissue-resident macrophage found in the sinusoids of the liver with an important role in gastrointestinal immune defense. lipid-carrying particles consisting of membrane phospholipids, free cholesterol, and proteins surrounding a core of triacylglycerols and cholesteryl esters. Lipoproteins are the major carriers of lipids in blood. a set of correlated metabolic risk factors: increased waist circumference, hypertension, hyperglycemia, hypertriglyceridemia, and low HDL. The presence of metabolic syndrome components is strongly associated with increased risk for cardiovascular disease, stroke, type 2 diabetes, non-alcoholic fatty liver disease, and other chronic diseases. specialized type of macrophage found in the central nervous system; important for central nervous system immunity, neuronal development, and synapse maintenance. form of selective autophagy used by cells to clear damaged or unnecessary mitochondria. molecules that signal the presence of pathogens, including those unique to microbes, such as lipopolysaccharide (LPS), while others are common molecules found in abnormal locations, such as cytosolic double-stranded DNA. host receptors that specifically recognize molecules indicating the presence of pathogens or other dangers and, in response, initiate signaling cascades to initiate immune responses. Major classes of PRRs include the Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I-like receptors (RLRs), and C-type lectin receptors (CLRs). mechanism of lytic, inflammatory cell death in immune cells. Pyroptosis involves caspase-mediated cleavage of gasdermins, which then assemble into a pore in the cell membrane, leading to cell lysis. strongly oxidizing molecules derived from oxygen, including superoxide (O2●–), hydroxyl radicals (●OH), and hydrogen peroxide (H2O2). lipids containing a backbone derived from the amino alcohol sphingosine. Major biological classes of sphingolipids include ceramides, sphingomyelins, cerebrosides, and globosides. family of membrane-bound receptors that sense PAMPs or noninfectious danger signals and activate signaling pathways leading to immune responses.