The Roles of Endoplasmic Reticulum in NLRP3 Inflammasome Activation

Abstract

The NLRP3 (nucleotide-binding domain, leucine-rich-repeat-containing family, pyrin domain-containing 3) inflammasome senses pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), and activates caspase-1, which provokes release of proinflammatory cytokines such as interleukin-1β (IL-1β) and IL-18 as well as pyroptosis to engage in innate immune defense. The endoplasmic reticulum (ER) is a large and dynamic endomembrane compartment, critical to cellular function of organelle networks. Recent studies have unveiled the pivotal roles of the ER in NLRP3 inflammasome activation. ER–mitochondria contact sites provide a location for NLRP3 activation, its association with ligands released from or residing in mitochondria, and rapid Ca2+ mobilization from ER stores to mitochondria. ER-stress signaling plays a critical role in NLRP3 inflammasome activation. Lipid perturbation and cholesterol trafficking to the ER activate the NLRP3 inflammasome. These findings emphasize the importance of the ER in initiation and regulation of the NLRP3 inflammasome.

The Molecular Mechanisms Underlying Mitochondria-Associated Endoplasmic Reticulum Membrane-Induced Insulin Resistance

“…Pharmacological relief of hypothalamic ER stress can reverse these metabolic alterations (130). Similarly, Brenda et al found that, following palmitic acid treatment, ER stress was induced only after MFN2 downregulation (30). These results indicate that ER stress may be the key pathway through which impaired MAM integrity leads to defects in hypothalamic insulin signaling.…”

“…MAMs are now known to be specialized lipid raft-like regions. These lipid microdomains are a dynamic assemblage of sphingolipids and cholesterol that can move within the fluid lipid bilayer and function as platforms for the attachment of proteins during signal transduction (30). These proteins can be enzymes, transporters, kinases, ion channels, or phosphatases (9), indicating that MAMs participate in various cellular processes, such as calcium homeostasis, lipid metabolism, mitochondrial physiology, ER stress, and inflammation.…”

“…These proteins can keep the ER-mitochondria contact at a proper distance. Deficiencies in tethering proteins, such as PDZD8, were recently reported to significantly reduce mitochondrial Ca 2+ import and impair cytosolic Ca 2+ dynamics (30). On the one hand, mitochondrial Ca 2+ uptake protects cells from significant Ca 2+ fluctuations and maintains Ca 2+ signaling.…”

Chemical Modulation of Mitochondria–Endoplasmic Reticulum Contact Sites

“…Quercetin can therefore influence TXNIP function, especially the MERCs-related one, which is important for inflammatory response. Indeed, TXNIP accumulates at MERCs in response to oxidative stress and mediates production of interleukin (IL)-1β [129,133,134].…”

The NFκB Antagonist CDGSH Iron-Sulfur Domain 2 Is a Promising Target for the Treatment of Neurodegenerative Diseases

“…Moreover, after activation of NLRP3 inflammasomes, advanced cytokine loops (IL-1β, IL-18) are subsequently formed, which can then stimulate the generation of proinflammatory cascades and eventually establish a vicious cycle between inflammation and mitochondrial dysfunction. NFκB-regulated NLRP3 inflammasomes activation involves the following critical organelles significant to cellular function: mitochondria, ER membranes, and MAMs [ 39 ].…”