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In the context of NLRP3 Inflammasome Activation, activators may cause relocalization to endosomal or Golgi compartments. The distinct changes in endosomal composition lead to the activation of the NLRP3 inflammasome. The activation of the NLRP3 inflammasome is mediated by PtdIns4P on the dispersed trans-Golgi network. The activation of NLRP3 and pyrin inflammasomes is mediated by Histone deacetylase 6 (HDAC6) through a mechanism similar to an aggresome.
The mechanism of NLRP3 activation is complex and indistinct, including Kalium efflux, Calcium signaling, mitochondrial dysfunction, reactive oxygen species production, lysosomal leakage, and trans-Golgi disassembly
NLRP3 Inflammasome Activation is a two-step process.
The first step is priming. Activated
lead to the activation of the NFKB pathway and subsequent transcription. This upregulates the expression of NLRP3 Inflammasome, Pro-Interleukin-1 (IL-1) beta (IL-1 beta) and Pro-Interleukin-18 (pro-IL-18)
Step 2 is triggered by a variety of PAMPs and Alarmins / Damage-associated molecular pattern (DAMPs), including extracellular ATP, viral RNA, and pore-forming toxins, as well as particles that cause assembling of NLRP3 Inflammasome with ASC and pro-caspase-1. This leads to a cleavage of the latter into its active form, which subsequently cleaves Pro-Interleukin-1 (IL-1) beta (IL-1 beta) and Pro-Interleukin-18 (pro-IL-18) into their mature cytokines
Palmitoylation of NLRP3 Inflammasome modulates inflammasome activation and inflammatory bowel disease development. NLRP3 palmitoylation is mediated by Palmitoyltransferase ZDHHC17 and it promotes NLRP3 Inflammasome Activation. 2-bromopalmitate blocks the [palmitoylation] and NLRP3 Inflammasome Activation. It suppresses NLRP3-mediated colitis in mice.
NLRP3 Inflammasome interacts with the adaptor protein ASC to activate caspase-1 in inflammasomes , protein complexes responsible for the maturation and secretion of Interleukin-1 (IL-1) beta (IL-1F2) and Interleukin-18 (IL-18)
Orchestration of NLRP3 Inflammasome Activation by Ion Fluxes
Typically, the NLRP3 inflammasome activation mechanism entails two steps: priming (step 1) and activation (step 2). Step 1 is carried out through Pattern Recognition Receptors (PRRs) signals, including Toll-Like Receptors (TLRs) (e.g., CD284 (Toll-Like Receptor 4 (TLR-4)) and muramyl dipeptide (MDP) / NLRC2 / NOD2 (NOD-like receptor family CARD Domain-Containing Protein 2), as well as activation and cytokines such as Tumor Necrosis Factor alfa (TNF-alfa) / TNF receptor superfamily (TNFRSF). These signals function through activating the NFKB-dependent pathway, thus upregulating the expression of NLRP3, Pro-Interleukin-1 (IL-1) beta (IL-1 beta), and Pro-Interleukin-18 (pro-IL-18), which empower NLRP3 and promote inflammasome assembly.
NLRP3 Inflammasome has many activators. It plays a role in disease immunopathology and can be triggered by pathogens. Its protective role is unclear
NLRP3 Inflammasome responds to stress signals. The activation mechanism is not fully known. Mitochondria may be involved. The activation of the NLRP3 inflammasome requires the mitochondrial electron transport chain. The activation of the Nlrp3 inflammasome necessitates the presence of mitochondrial cardiolipin.
Iyer et al. 2013 Immunity 39: 311-323
K⁺ efflux was once thought essential. New findings show activation without K⁺ efflux. The activation of the NLRP3 inflammasome by bacterial toxins and particulate matter is commonly triggered by K+ efflux. The detection of low intracellular potassium by NLRP3 leads to a stable open structure, which facilitates the activation of the inflammasome.
Alarmins / Damage-associated molecular pattern (DAMPs), Pathogen-Associated Molecular Patterns (PAMPS), Reactive Oxygen Stress (ROS), and Cathepsin B can activate the NLRP3 inflammasome
SCFAs binding to G-Protein Coupled Receptor 43 (GPR43) on colonic epithelial cells stimulates Kalium efflux and hyperpolarization, which lead to NLRP3 inflammasome activation
NLRP3 inflammasome-mediated caspase-1 activation in DCs is required for IL-1 beta dependent antitumor T cell response
Aberrant NLRP3 Inflammasome Activation has been shown associations with severe diseases (e.g., neurodegenerative, autoimmune, autoinflammatory, and metabolic diseases and cancers)
Aberrant activation of NLRP3 inflammasome has been shown to contribute to Inflammatory Bowel Disease (IBD) pathogenesis
see also:
Autoinflammatory diseases
Crohn's disease (CD) & NLRP3 Inflammasome
Hepatic Stellate Cells (HSC)
Inflammasomes
Mitochondrial Dysfunction
NLRP3 Inflammasome