Cryopyrin activates the inflammasome in response to toxins and ATP

Mariathasan, Sanjeev; Weiss, David S.; Newton, Kim; McBride, Jacqueline; O’Rourke, Karen; Roose-Girma, Meron; Lee, Wyne P.; Weinrauch, Yvette; Monack, Denise M.; Dixit, Vishva M.

doi:10.1038/nature04515

Cited by 2,637 publications

(2,514 citation statements)

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“…79 The generation of ASC (a crucial NALP/caspase-1 adaptor)-deficient mice demonstrated that ATP-mediated caspase-1 activation requires ASC and is therefore probably dependent on the activation of a NALP protein. 80 This hypothesis was indeed confirmed in studies using NALP3-deficient mice [81][82][83] (Figure 4). Another study suggested that NALP3 (also known as cryopyrin) is required for caspase-1 activation by bacterial RNA or the small antiviral compounds R848 and R837.…”

Section: Toxins and Agents Inducing Potassium Efflux Activate The Nalsupporting

confidence: 60%

“…84 Other agents that decrease intracellular potassium levels such as the potassium ionophore nigericine and maitotoxin, a potent marine toxin, depend on the NALP3-based inflammasome for caspase-1 activation. 81 NALP3 and ASC are also required for caspase-1 activation by the Gram-positive bacteria Staphylococcus aureus and Listeria monocytogenes. 81,85 L. monocytogenes-mediated caspase-1 activation requires the bacterial toxin listeriolysin O (LLO).…”

Section: Toxins and Agents Inducing Potassium Efflux Activate The Nalmentioning

confidence: 99%

“…Whether this toxin and the unidentified caspase-1-activating factor from S. aureus are dependent on potassium efflux or NALP3 activation, requires further investigations. 81 …”

Section: Toxins and Agents Inducing Potassium Efflux Activate The Nalmentioning

confidence: 99%

“…activate caspase-1 following S. typhimurium infection. 81,83 Similarly Francisella tularensis requires ASC to activate caspase-1 and to trigger a competent immune response. 96 Activation of ASC and caspase-1 by F. tularensis is dependent on the internalization and phagosome escape.…”

Section: Nalp3 and Activation Of The Adaptive Immune Systemmentioning

confidence: 99%

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Inflammatory caspases and inflammasomes: master switches of inflammation

2006

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Fifteen years have passed since the cloning and characterization of the interleukin-1b-converting enzyme (ICE/caspase-1), the first identified member of a family of proteases currently known as caspases. Caspase-1 is the prototypical member of a subclass of caspases involved in cytokine maturation termed inflammatory caspases that also include caspase-4 caspase -5, caspase -11 and caspase -12. Efforts to elucidate the molecular mechanisms involved in the activation of these proteases have uncovered an important role for the NLR family members, NALPs, NAIP and IPAF. These proteins promote the assembly of multiprotein complexes termed inflammasomes, which are required for activation of inflammatory caspases. This article will review some evolutionary aspects, biochemical evidences and genetic studies, underlining the role of inflammasomes and inflammatory caspases in innate immunity against pathogens, autoinflammatory syndromes and in the biology of reproduction. Inflammatory CaspasesThe history of caspases began with the identification of an aspartate-specific protease activity involved in the conversion of the 31 kDa proIL-1b precursor to its active 17 kDa biologically active form, 1,2 and the identification of caspase-1 as the protease responsible for proIL-1b maturation. 3,4 The subsequent discovery of ced-3, that shares similarities with caspase-1 and which is involved in programmed cell death (PCD) in Caenorhabditis elegans, suggested that caspases might play fundamental roles in apoptosis. 5 As reviewed in the papers accompanying this issue of Cell Death and Differentiation, the role of apoptotic caspases in C. elegans and in vertebrates is crucial and deal with many facets of cell biology, development and diseases. In this review, we will focus on a subset of caspases present only in vertebrates and known as inflammatory caspases.Inflammatory caspases (also known as group I caspases) are encoded by three main genes in humans caspase-1, caspase-4 and caspase-5 and three main genes in mouse, caspase-1, caspase-11 and caspase-12. 6,7 In mammals, these caspases are characterized by the presence of a CARD domain at the N-terminus (Figure 1a). Human, chimp and mouse inflammatory caspases share significant similarity and are organized in a single locus (Figure 1c). Phylogenetic analysis of the conserved CARD domain suggests that the inflammatory caspases can be separated in evolutionaryrelated clusters (Figure 1b). The caspase-1 cluster contains caspase-1 and four other genes encoding decoy caspases: cop, inca1, inca2 and iceberg. These decoy caspase-1-like genes are absent in the mouse genome, suggesting that they have arisen recently by duplication of caspase-1. Although human and mouse caspase-1 are likely orthologues, sequence analysis suggests that human caspase-4 and caspase-5 have originated from a duplication of caspase-11. 7 However, the human caspase-12 gene, which in the chimp genome contains an SHG box important for it enzymatic activity, 8 evolved towards an enzymatically inactive form at some stage...

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Section: Toxins and Agents Inducing Potassium Efflux Activate The Nalsupporting

confidence: 60%

Section: Toxins and Agents Inducing Potassium Efflux Activate The Nalmentioning

confidence: 99%

“…Whether this toxin and the unidentified caspase-1-activating factor from S. aureus are dependent on potassium efflux or NALP3 activation, requires further investigations. 81 …”

Section: Toxins and Agents Inducing Potassium Efflux Activate The Nalmentioning

confidence: 99%

Section: Nalp3 and Activation Of The Adaptive Immune Systemmentioning

confidence: 99%

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Inflammatory caspases and inflammasomes: master switches of inflammation

2006

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“…C57Bl6/J (wild-type) mice were bred from our colony, purchased from Jackson Laboratories or received from the National Institute of Aging Rodent colony. Nlrp3 −/− have been previously described and were bred in our facility, along with their wild-type controls 29 . LysM-Cre and mT/mG mice were bred in our facility.…”

Section: Methodsmentioning

confidence: 99%

Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing

Camell

Sander

Spadaro

et al. 2017

Nature

333

320

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Catecholamine-induced lipolysis, the first step in generation of energy substrates through hydrolysis of triglycerides (TGs) 1, declines with age 2,3. The defect in mobilization of free fatty acids (FFA) in elderly is accompanied with increased visceral adiposity, lower exercise capacity, failure to maintain core body temperature during cold stress, and reduced ability to survive starvation. While catecholamine signaling in adipocytes is normal in elderly, how lipolysis is impaired in aging remains unknown 2,4. Here we uncover that the adipose tissue macrophages (ATMs) regulate age-related reduction in adipocyte lipolysis by lowering the bioavailability of norepinephrine (NE). Unexpectedly, unbiased whole transcriptome analyses of adipose macrophages revealed that aging upregulates genes controlling catecholamine degradation in an NLRP3 inflammasome-dependent manner. Deletion of NLRP3 in aging restored catecholamine-induced lipolysis through downregulation of growth differentiation factor-3 (GDF3) and monoamine oxidase-a (MAOA) that is known to degrade NE. Consistent with this, deletion of GDF3 in inflammasome-activated macrophages improved lipolysis by decreasing MAOA and caspase-1. Furthermore, inhibition of MAOA reversed age-related reduction in adipose tissue NE concentration and restored lipolysis with increased levels of key lipolytic enzymes, adipose triglyceride lipase (ATGL) and hormone sensitive lipase (HSL). Our study reveals that targeting neuro-innate signaling between sympathetic nervous system and macrophages may offer new approaches to mitigate chronic inflammation-induced metabolic impairment and functional decline.

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