Extracellular ATP Activates the NLRP3 Inflammasome and Is an Early Danger Signal of Skin Allograft Rejection

Amores, J.; Barberà-Cremades, María; Martínez, Carlos; Pons, J.A.; Revilla-Nuin, Beatriz; Martı́nez-Alarcón, L.; Virgilio, Francesco Di; Parrilla, Pascual; Baroja‐Mazo, Alberto; Pelegrı́n, Pablo

doi:10.1016/j.celrep.2017.11.079

Cited by 142 publications

(123 citation statements)

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“…Among the diverse exogenous and endogenous stimulatory damaged‐associated molecular patterns (DAMPs) and pathogen‐associated molecular patterns, PRR (TLR and NLR) ligands and IL‐1α have been reported to act as priming signals . As second signals, adenine triphosphate (ATP), misfolded proteins, crystalline substances, pore‐forming toxins, particulate matter, and viral RNA are the most common inducers of NLRP3 inflammasome activation . In neurodegenerative disorders, microglial NLRP3 inflammasome becomes activated by sensing different endogenous signals or proteins, such as amyloid‐β, α‐synuclein, superoxide dismutase, prion protein, ATP, and members of the complement pathways .…”

Section: Nlrp3: Structure Activation and Function In Pdmentioning

confidence: 99%

Targeting the Microglial NLRP3 Inflammasome and Its Role in Parkinson's Disease

et al. 2019

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Excessive activation of microglia and subsequent release of proinflammatory cytokines play a crucial role in neuroinflammation and neurodegeneration in Parkinson's disease (PD). Components of the nucleotide‐binding oligomerization domain and leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome complex, leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3, caspase‐1, and apoptosis‐associated speck‐like protein containing a CARD, are highly expressed in activated microglia in PD patient brains. Findings suggest that neurotoxins, aggregation of α‐synuclein, mitochondrial reactive oxygen species, and disrupted mitophagy are the key regulators of microglial leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome activation and release of interleukin‐1β and interleukin‐18 caspase‐1‐mediated pyroptotic cell death in the substantia nigra of the brain. Although this evidence suggests the leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome may be a potential drug target for treatment of PD, the exact mechanism of how the microglia sense these stimuli and initiate leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome signaling is unknown. Here, the molecular mechanism and regulation of microglial leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome activation and its role in the pathogenesis of PD are discussed. Moreover, the potential of both endogenous and synthetic leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome modulators, long noncoding RNA, microRNA to develop novel therapeutics to treat PD is presented. Overall, we recommend that the microglial leucine‐rich‐repeat‐ and pyrin‐domain‐containing 3 inflammasome can be a potential target for PD treatment. © 2019 International Parkinson and Movement Disorder Society

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Section: Nlrp3: Structure Activation and Function In Pdmentioning

confidence: 99%

Targeting the Microglial NLRP3 Inflammasome and Its Role in Parkinson's Disease

et al. 2019

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“…Most published studies of P2X7 receptors have focused on the pro-inflammatory 'pore' function of this receptor, but the requirement for high concentrations (>100 μM, but usually 1-5 mM depending on ambient divalent cations) of extracellular ATP for pore opening would be rarely achieved in physiological conditions, suggesting that this receptor has an alternative non-inflammatory function in the CNS. Only in pathological conditions, where the extracellular ATP level is elevated, as measured using in vivo bioluminescence technique, may it be high enough to trigger P2X7-mediated pro-inflammatory downstream effects (Di Virgilio et al, 2016;Amores-Iniesta et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

P2X7 as a scavenger receptor for innate phagocytosis in the brain

Wiley

2018

British J Pharmacology

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The P2X7 receptor has been widely studied for its ATP-induced pro-inflammatory effect, but in the absence of a ligand, P2X7 has a second function as a scavenger receptor, which is active in the development of the human brain. The scavenger activity of P2X7 is only evident in the absence of serum but is fully active in cerebrospinal fluid. P2X7 on the cell surface is present as a membrane complex, and an attachment to non-muscle myosin of the cytoskeleton is required for particle engulfment. Selective antagonists of P2X7 pro-inflammatory function have little effect on phagocytosis, but inheritance of a variant haplotype spanning the P2RX7 and P2RX4 genes has been associated with loss of P2X7-mediated phagocytosis. Recent studies in mice suggest that the innate phagocytosis mediated by P2X7 receptors declines with ageing. Thus, defective P2X7-mediated phagocytosis may contribute to age-related neuro-degenerative diseases including Alzheimer's disease, age-related macular degeneration and primary progressive multiple sclerosis.

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“…Pyrin mutations associated with familial Mediterranean fever (FMF) [50] and the NLRC4 gain of function mutations that mediate the Macrophage Activation Syndrome (MAS) [51] are all characterised by systemically elevated IL-18 levels. Moreover, the release of damage associated signals such as ATP in transplantation can lead to P2X7Rmediated activation of the inflammasome inducing the release of IL-18, but not IL-1β, which in turn plays an important role in allograft rejection through IFN-γ production and CD8 + T cell proliferation [52]. Inflammasomes are also activated during the progression of sterile inflammatory diseases including atherosclerosis, metabolic and neuro-inflammatory disorders where IL-18 is an important driver [53].…”

Section: Discussionmentioning

confidence: 99%

Priming is dispensable for NLRP3 inflammasome activation in human monocytes

Gritsenko¹,

Martín-Sánchez³

et al. 2020

Preprint

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Interleukin (IL)-1 family of cytokines modulate immune responses during infection and inflammation. IL-18 and IL-1β are members of the IL-1 family, which contribute to inflammatory conditions such as rheumatoid arthritis and Alzheimer's disease. and IL-1β are produced as inactive precursors that are activated by large macromolecular complexes called inflammasomes upon sensing damage or pathogenic signals. Canonical NLRP3 inflammasome activation is regarded to require a priming step that causes NLRP3 and IL-1β gene upregulation, and also NLRP3 posttranslational licencing. A subsequent activation step leads to the assembly of the inflammasome and the cleavage of pro-IL-18 and pro-IL-1β by caspase-1 into their mature forms, allowing their release. Here we show that in primary human monocytes, the initial priming step is dispensable to form an active NLRP3 inflammasome. We found that, in the absence of priming, the NLRP3 activator nigericin caused the processing and release of constitutively expressed IL-18. Another IL-1 family member, IL-37, is constitutively cleaved but the release of its mature form was mediated by inflammasome activation, also in the absence of a priming step. This NLRP3 activation was characterised by ASC oligomerisation as well as caspase-1 and GSDMD cleavage and was blocked by the NLRP3 inhibitor MCC950 and in NLRP3 deficient cells. IL-18 and IL-37 release were impaired in GSDMD deficient THP-1s, suggesting 2 that pyroptosis is required for release of these cytokines. This work highlights the readiness of the NLRP3 inflammasome to assemble in the absence of priming and hence contribute to sterile inflammatory processes in health and disease. Significance StatementThe NLRP3 inflammasome is a driver of inflammation through the processing of Interleukins (IL)-1β and IL-18. Human monocytes coordinate the innate immune response through inflammasome activation following exposure to pathogens and damage signals. We currently think of NLRP3 activation as a 2 step process: priming (NLRP3 gene upregulation and post-translational licencing) and assembly. Here we show that the priming step is dispensable for NLRP3 inflammasome activation in human monocytes. The second signal alone is sufficient for caspase-1 activation, leading to cell death and the release of the constitutively expressed IL-18 and mIL-37.This reveals that in human monocytes, the NLRP3 inflammasome is already licenced and able to quickly assemble to mount an inflammatory response.

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Extracellular ATP Activates the NLRP3 Inflammasome and Is an Early Danger Signal of Skin Allograft Rejection

Cited by 142 publications

References 55 publications

Targeting the Microglial NLRP3 Inflammasome and Its Role in Parkinson's Disease

Targeting the Microglial NLRP3 Inflammasome and Its Role in Parkinson's Disease

P2X7 as a scavenger receptor for innate phagocytosis in the brain

Priming is dispensable for NLRP3 inflammasome activation in human monocytes

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