An update on the regulatory mechanisms of NLRP3 inflammasome activation

Abstract

The NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome is a multiprotein complex involved in the release of mature interleukin-1β and triggering of pyroptosis, which is of paramount importance in a variety of physiological and pathological conditions. Over the past decade, considerable advances have been made in elucidating the molecular mechanisms underlying the priming/licensing (Signal 1) and assembly (Signal 2) involved in NLRP3 inflammasome activation. Recently, a number of studies have indicated that the priming/licensing step is regulated by complicated mechanisms at both the transcriptional and posttranslational levels. In this review, we discuss the current understanding of the mechanistic details of NLRP3 inflammasome activation with a particular emphasis on protein-protein interactions, posttranslational modifications, and spatiotemporal regulation of the NLRP3 inflammasome machinery. We also present a detailed summary of multiple positive and/or negative regulatory pathways providing upstream signals that culminate in NLRP3 inflammasome complex assembly. A better understanding of the molecular mechanisms underlying NLRP3 inflammasome activation will provide opportunities for the development of methods for the prevention and treatment of NLRP3 inflammasome-related diseases.

The 3-Year Effect of the Mediterranean Diet Intervention on Inflammatory Biomarkers Related to Cardiovascular Disease

“…Appearance and progression of atherosclerosis are related to the oxidation of lipids in low-density lipoprotein particles (LDL). Recent studies indicate that the cell surface receptor CD36 facilitates internalization of oxidized LDL (oxLDL) and intracellular conversion of oxLDL to cholesterol crystals which are able to activate the Nod-like receptor protein (NLRP) 3 inflammasome in vitro experiments through its bond to toll-like receptors (TLRs) [ 2 , 3 , 4 , 5 , 6 ]. This process leads to the recruitment of leukocytes and a higher expression of adhesion molecules such as E-selectin and VCAM-1 on the endothelial surface of the artery [ 7 ].…”

“…This process leads to the recruitment of leukocytes and a higher expression of adhesion molecules such as E-selectin and VCAM-1 on the endothelial surface of the artery [ 7 ]. Leukocyte activation takes place by chemokines (monocyte chemoattractant protein-1 (MCP-1), regulated on activation normal T cells expressed and secreted (RANTES), interferon gamma-induced protein 10 (IP-10)) and chemokine receptors (CCR2, CCR5, CXCR2), which attract monocytes, neutrophils, dendritic cells (DCs) and T cells into the intima [ 5 , 8 , 9 , 10 , 11 ] and induce inflammasome activation (Nod-like receptor protein (NLRP) in macrophages [ 4 , 6 ]. This activation leads to the maturation of caspase-1 and the processing of its substrates, interleukin (IL)-1β and IL-18 [ 2 , 6 , 12 ], and finally IL-1β promotes the development of lipid plaque and also destabilizes it [ 6 , 13 ].…”

“…Table S6: Pearson’s correlation of 3-year changes in cytokines in the three groups in the Predimed study. References [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 ] are cited in the supplementary materials.…”

Chemical Modulation of the 1-(Piperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazole-2-one Scaffold as a Novel NLRP3 Inhibitor

“…Each of these domains play a different role. The role of the LRR domain is still to be fully clarified: LRR appears to be dispensable for NLRP3 activation [ 4 ], however, by binding to NIMA-related kinase 7 (NEK7), it facilitates the ATP-dependent activation of NLRP3 [ 2 , 5 ]; the NACHT domain is mainly responsible for oligomerization and possesses ATP-binding and hydrolysis abilities [ 6 ]; finally, the PYD domain interacts with ASC through homotypic (PYD–PYD) interactions [ 7 ]. NLRP3 expression is induced following the stimulation by danger-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs) of Toll-like receptors (TLRs), such as TLR4 receptors, or cytokine receptors, such as TNF receptor.…”

“…NLRP3 usually needs a second signal, generally referred to as an activation signal , to be fully activated. Different signals can lead to inflammasome activation [ 7 , 11 , 12 , 13 ]. Nigericin, ATP, molecular particulates and crystals induce, through different mechanisms, a K + efflux that is considered a common trigger for NLRP3 activation [ 14 ].…”