Increasing complexity of NLRP3 inflammasome regulation

Moretti, Julien; Blander, J. Magarian

doi:10.1002/jlb.3mr0520-104rr

Cited by 75 publications

(60 citation statements)

References 109 publications

(221 reference statements)

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“…The inactive form of NLRP3 resides on ER and translocates on mitochondrial outer membrane upon activation [ [148] , [149] , [150] , [151] ]. NLRP3 located in mitochondria interacts with mitochondrial ASC to assemble inflammasome or with mitochondrial antiviral signaling protein (MAVS) [ 152 ]. MAVS is a mitochondrial adaptor protein which mediates the translocation and association of NLRP3 to mitochondria.…”

Section: Mitochondrial Ros Systems Serve As the Central Hub For Connementioning

confidence: 99%

“…Furthermore, ROS activate NLRP3 inflammasome via direct and indirect ways. Studies found that increased ROS level induced mitochondrial DNA damage is also an indirect pathway for NLRP3 inflammasome activation by ROS [ 152 , 154 ]. In high level of ROS, thioredoxin-interacting protein (TXNIP) is dissociated with TRX and activates NLRP3 inflammasome [ 157 ].…”

Section: Mitochondrial Ros Systems Serve As the Central Hub For Connementioning

confidence: 99%

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ROS systems are a new integrated network for sensing homeostasis and alarming stresses in organelle metabolic processes

et al. 2020

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Reactive oxygen species (ROS) are critical for the progression of cardiovascular diseases, inflammations and tumors. However, the mechanisms of how ROS sense metabolic stress, regulate metabolic pathways and initiate proliferation, inflammation and cell death responses remain poorly characterized. In this analytic review, we concluded that: 1) Based on different features and functions, eleven types of ROS can be classified into seven functional groups: metabolic stress-sensing, chemical connecting, organelle communication, stress branch-out, inflammasome-activating, dual functions and triple functions ROS. 2) Among the ROS generation systems, mitochondria consume the most amount of oxygen; and nine types of ROS are generated; thus, mitochondrial ROS systems serve as the central hub for connecting ROS with inflammasome activation, trained immunity and immunometabolic pathways. 3) Increased nuclear ROS production significantly promotes cell death in comparison to that in other organelles. Nuclear ROS systems serve as a convergent hub and decision-makers to connect unbearable and alarming metabolic stresses to inflammation and cell death. 4) Balanced ROS levels indicate physiological homeostasis of various metabolic processes in subcellular organelles and cytosol, while imbalanced ROS levels present alarms for pathological organelle stresses in metabolic processes. Based on these analyses, we propose a working model that ROS systems are a new integrated network for sensing homeostasis and alarming stress in metabolic processes in various subcellular organelles. Our model provides novel insights on the roles of the ROS systems in bridging metabolic stress to inflammation, cell death and tumorigenesis; and provide novel therapeutic targets for treating those diseases. (Word count: 246).

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Section: Mitochondrial Ros Systems Serve As the Central Hub For Connementioning

confidence: 99%

Section: Mitochondrial Ros Systems Serve As the Central Hub For Connementioning

confidence: 99%

ROS systems are a new integrated network for sensing homeostasis and alarming stresses in organelle metabolic processes

et al. 2020

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“…The most studied and the best known inflammasome is NLRP3. The NLRP3 inflammasome consists of a sensor (NLRP3), an adaptor molecular apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) and a precursor of effector molecule caspase 1, pro-caspase-1 [ 70 , 71 ]. It seems that the limiting factor for the activation of the NLRP3 inflammasome is the expression of NLRP3 itself [ 72 ].…”

Section: Nlrp3 Inflammasomementioning

confidence: 99%

Galectin-3 in Inflammasome Activation and Primary Biliary Cholangitis Development

Arsenijević

Stojanović

Milovanović

et al. 2020

IJMS

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Primary biliary cholangitis (PBC) is a chronic inflammatory autoimmune liver disease characterized by inflammation and damage of small bile ducts. The NLRP3 inflammasome is a multimeric complex of proteins that after activation with various stimuli initiates an inflammatory process. Increasing data obtained from animal studies implicate the role of NLRP3 inflammasome in the pathogenesis of various diseases. Galectin-3 is a β-galactoside-binding lectin that plays important roles in various biological processes including cell proliferation, differentiation, transformation and apoptosis, pre-mRNA splicing, inflammation, fibrosis and host defense. The multilineage immune response at various stages of PBC development includes the involvement of Gal-3 in the pathogenesis of this disease. The role of Galectin-3 in the specific binding to NLRP3, and inflammasome activation in models of primary biliary cholangitis has been recently described. This review provides a brief pathogenesis of PBC and discusses the current knowledge about the role of Gal-3 in NLRP3 activation and PBC development.

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“…It was also shown that mitochondrial dysfunction due to TXNIP played a key role in NLRP3 activation (42,43). In order to investigate whether RAGE-TXNIP axis was implied in inflammasome complex activation, we measured NLRP3 protein expression as well as the activation of caspase-1 and the production of IL-1β (44). In LPS-primed microglia, Aβ treatment significantly increased NLRP3 protein and cleaved (activated) caspase-1 (Fig.…”

mentioning

confidence: 89%

Rage-txnip Axis Drives Inflammation in Alzheimer`s by Targeting aβ to Mitochondria in Microglia

Perrone

Abate

Uberti

et al. 2020

Preprint

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Alzheimer’s disease (AD) is the most common form of dementia characterized by progressive memory loss and cognitive decline. Although neuroinflammation and oxidative stress are well-recognized features of AD, their correlations with the early molecular events characterizing the pathology are not yet well clarified. Here we demonstrated the role of RAGE-TXNIP axis in neuroinflammation in relation to amyloid-beta (Aβ) burden in both invivo and in-vitro models. In the hippocampus of 5xFAD mice, microglial activation correlates with increased TXNIP expression, and TXNIP silencing or its pharmacological inhibition prevented the neuroinflammation in those mice. TXNIP increased expression has been found also in human subjects affected by AD and other dementia when plasma samples were analyzed, suggesting TXNIP as a putative biomarker of neurodegeneration and cognitive decline. To better elucidate whether a mechanistic link between RAGE-TXNIP axis and AD exist, we investigated how TXNIP is involved in Aβ intracellular trafficking downstream RAGE. Indeed, TXNIP is an α-arrestin protein involved in endocytosis. We found TXNIP associated to RAGE and Aβ. RAGE-TXNIP axis was required for targeting Aβ into mitochondria, as shown in primed primary microglia exposed to Aβ dimers. Silencing of TXNIP or inhibition of RAGE activation reduced Aβ transport from the cellular surface to mitochondria. Detrimental effect of Aβ in mitochondria has been also confirmed by evaluating increased mitochondrial- and intracellular- oxidative stress. When RAGE-TXNIP axis is down-regulated, mitochondrial functionality was restored and Aβ toxicity was mitigated. Furthermore, Aβ transport into mitochondria and subsequent mitochondrial dysfunction drove inflammation in microglia cells via NLRP3 inflammasome activation, and down-regulation of RAGE-TXNIP axis was able to efficiently mitigate Aβ proinflammatory effect. Overall this data suggest RAGE-TXNIP axis is required for NLRP3 inflammasome activation induced by Aβ in microglia.Our work shed light on novel mechanism of action of RAGE-TXNIP axis in microglia, which is intertwined with Aβ and ultimately causes inflammation, suggesting TXNIP as a druggable target to be better deepened for AD.

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Increasing complexity of NLRP3 inflammasome regulation

Cited by 75 publications

References 109 publications

ROS systems are a new integrated network for sensing homeostasis and alarming stresses in organelle metabolic processes

ROS systems are a new integrated network for sensing homeostasis and alarming stresses in organelle metabolic processes

Galectin-3 in Inflammasome Activation and Primary Biliary Cholangitis Development

Rage-txnip Axis Drives Inflammation in Alzheimer`s by Targeting aβ to Mitochondria in Microglia

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