The adaptor ASC has extracellular and 'prionoid' activities that propagate inflammation

Franklin, Bernardo S.; Bossaller, Lukas; Nardo, Dominic De; Ratter, Jacqueline M.; Stutz, Andrea; Engels, Gudrun; Brenker, Christoph; Nordhoff, Mark; Mirandola, Sandra R.; Al‐Amoudi, Ashraf; Mangan, Matthew; Zimmer, Sebastian; Monks, Brian G.; Fricke, Martin; Schmidt, Reinhold E.; Espevik, Terje; Jones, Bernard Edward; Jarnicki, Andrew G.; Hansbro, Philip M.; Busto, Patricia; Marshak‐Rothstein, Ann; Hornemann, Simone; Aguzzi, Adriano; Kastenmüller, Wolfgang; Latz, Eicke

doi:10.1038/ni.2913

Cited by 639 publications

(762 citation statements)

References 52 publications

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“…Catalytically active ASC specks are released into the extracellular space following cytolytic execution of pyroptosis. 25 Notably, analysis of ASC specks in BM plasma from LR-MDS specimens (n 5 6) confirmed a profound increase in the percentage and MFI of ASC specks in MDS vs normal BM plasma (n 5 3) (mean, 36.2 6 1.4 vs 6.0 6 8.4; Figure 1G). Finally, immunofluorescence and flow cytometry analyses of other hematologic malignancies suggest that inflammasome activation is specific for MDSs (supplemental Figure 1).…”

Section: Mds Hspcs Manifest Inflammasome Activation and Pyroptosismentioning

confidence: 77%

“…53,54 Additionally, our findings that catalytically active pyroptotic ASC specks are released from the cytosol into the extracellular space suggests that specks may further reinforce bystander inflammation in the microenvironment in a non-cell-autonomous fashion. 25,55 Importantly, NOX1/4 inhibition suppressed activation of the inflammasome and b-catenin both in MDS patient-derived BM-MNCs and in cells harboring varied classes and types of MDS founder gene mutations. Thus, S100A9 induces NOX1/4 to drive ROS-dependent inflammasome assembly, pyroptosis, and b-catenin activation, explaining the proliferation and inflammatory cell death manifest in MDSs.…”

Section: Discussionmentioning

confidence: 99%

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The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype

Basiorka¹,

McGraw²,

Eksioglu³

et al. 2016

Blood

273

313

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Key Points• Key biological features of MDSs are explained by NLRP3 inflammasome activation, which drives pyroptotic cell death and b-catenin activation.• Alarmin signals and founder gene mutations license this redox-sensitive inflammasome platform.Despite genetic heterogeneity, myelodysplastic syndromes (MDSs) share features of cytological dysplasia and ineffective hematopoiesis. We report that a hallmark of MDSs is activation of the NLRP3 inflammasome, which drives clonal expansion and pyroptotic cell death. Independent of genotype, MDS hematopoietic stem and progenitor cells (HSPCs) overexpress inflammasome proteins and manifest activated NLRP3 complexes that direct activation of caspase-1, generation of interleukin-1b (IL-1b) and IL-18, and pyroptotic cell death. Mechanistically, pyroptosis is triggered by the alarmin S100A9 that is found in excess in MDS HSPCs and bone marrow plasma. Further, like somatic gene mutations, S100A9-induced signaling activates NADPH oxidase (NOX), increasing levels of reactive oxygen species (ROS) that initiate cation influx, cell swelling, and b-catenin activation. Notably, knockdown of NLRP3 or caspase-1, neutralization of S100A9, and pharmacologic inhibition of NLRP3 or NOX suppress pyroptosis, ROS generation, and nuclear b-catenin in MDSs and are sufficient to restore effective hematopoiesis. Thus, alarmins and founder gene mutations in MDSs license a common redox-sensitive inflammasome circuit, which suggests new avenues for therapeutic intervention. (Blood. 2016;128(25):2960-2975

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Section: Mds Hspcs Manifest Inflammasome Activation and Pyroptosismentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype

Basiorka¹,

McGraw²,

Eksioglu³

et al. 2016

Blood

273

313

View full text Add to dashboard Cite

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“…La deuxième catégorie de signaux correspond à des structures particulaires comme l'amiante, la silice, les cristaux de cholestérol, l'amyloïde-et les liposomes qui, en s'accumulant dans les lysosomes après avoir été phagocytées, entraînent leur rupture et la libéra-tion de cathepsines et de Ca 2+ dans le cytosol [25]. Les specks, qui contiennent l'inflammasome, sont également libérés dans le milieu extracellulaire par les cellules pyroptotiques ; ils sont ensuite phagocytés par les macrophages, leur ingestion provoquant l'activation de l'inflammasome, par la déstabilisation des lysosomes, et celle de la caspase-1, par un recrutement direct, ce qui amplifie la réponse des cellules [26,27]. Les perturbateurs des fonctions mitochondriales forment une troisième catégorie de signaux.…”

Section: Les Voies De Signalisation Qui Contrôlent L'assemblage De L'unclassified

NLRP3, un inflammasome sous contrôle

Groslambert

2018

Med Sci (Paris)

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> La réponse immunitaire innée protège l'organisme par la détection rapide des agents pathogènes et des lésions via des récepteurs spéciali-sés, dont NLRP3. Celui-ci assemble un inflammasome, un complexe cytosolique de signalisation qui active la caspase-1, contrôle la libération de cytokines et de facteurs inflammatoires produits dans le cytosol comme les interleukines 1 / . Les pathologies inflammatoires associées à NLRP3, dont la goutte, révèlent la nécessité d'un contrôle étroit de son activité. Cette revue présente les avancées sur la signalisation du priming (ou amorçage) du complexe puis de son activation avec une attention particulière sur le rôle des modifications post-traductionnelles de NLRP3. < cytokines et d'autres facteurs intracellulaires pro-inflammatoires dont l'IL-1 La mort par pyroptose de cellules infectées permet d'éliminer en parallèle les niches de réplication des pathogènes intracellulaires. La structure des inflammasomes dits non-canoniques, associés à la caspase-11, ou 4 et 5 chez l'homme, reste mal connue. Les inflammasomes canoniques, qui sont eux, associés à la caspase-1, sont assemblés par des récepteurs cytosoliques de la famille des NLR (nucleotide-binding domain leucin-rich repeat) ou ALR (Aim2-like receptors). Ces récepteurs s'oligomérisent pour former une plateforme de nucléation pour des filaments formés par la protéine adaptatrice ASC (apoptosis-associated speck-like protein containing a CARD domain, aussi appelé PYCARD, CARD5, TMS1, Q9ULZ3), dont la surface permet, à son tour, la nucléation de filaments de pro-caspase-1 [4]. Ces inflammasomes forment des specks (ou structures ponctiformes) d'une taille de l'ordre du micron, visibles en microscopie, et qui sont uniques pour une cellule. NLRP3 (nucleotide-binding domain leucin-rich repeat [LRR] and pyrin-containing receptor 3, nommé également cryopyrin, CIAS1 [cold autoinflammatory syndrome 1 protein] ou NALP3 [NACHT, LRR and PYD domains-containing protein 3]) a été initialement décrit pour son association génétique avec des syndromes auto-inflammatoires héréditaires monogéniques dominants, nommés CAPS (cryopyrin-associated periodic syndrome) ou cryopyrinopathies [5]. Depuis, NLRP3 a été impliqué dans de nombreuses pathologies multifactorielles à composante inflammatoire, dont l'arthrite goutteuse, l'athérosclérose, le diabète de type 2 et la stéatose hépatique non-alcoolique [6,7]. Il est également impliqué dans plusieurs maladies neurodégénéra-tives, dont la sclérose en plaques et les maladies d'Alzheimer et de Parkinson, ainsi que dans les pathologies associées au vieillissement [6][7][8][9]. NLRP3 est aussi important au cours des infections par diffé-rents pathogènes. Il intervient en effet dans la reconnaissance de

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“…The most fascinating is the difference in the activator/scaffolding protein ratio. Apaf-1 and Dark are activated as 1:1 complexes with their activators (cytochrome c for Apaf-1 and Dronc CARD for is released from cells to facilitate caspase-1 activation in the extracellular space and transferred to new phagocytic cells to induce further inflammatory responses [51,52]. Interestingly, ASC speck also appears upon the activation of NLRC4.…”

Section: The Role Of Asc In Cytokine Maturation and Pyroptosismentioning

confidence: 99%

The NLRC4 inflammasome: The pieces of the puzzle are falling into place

Hafner-Bratkovič¹

2017

Inflammasome

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Inflammasomes are intracellular multiprotein platforms for the activation of inflammatory caspases. As components of the innate immune system, they play an important role in the fight against microbes. However, aberrant inflammasome activation has been implicated in auto-inflammatory syndromes. This review focuses on the NLRC4 inflammasome. This is perhaps not the most extensively studied, yet its mechanism of activation is by far the best understood. The NLRC4 inflammasome is activated by several proteins originating from intracellular bacteria, which are first sensed by receptors of the NAIP family. Activated NAIP binds NLRC4, which further recruits dormant NLRC4 molecules in a prion-like oligomerization event. NLRC4 enables a strong amplification of the signal, providing a fast and robust host response. The review also discusses peculiar NLRC4 inflammasome functions in promoting eicosanoid biosynthesis, actin reorganization, and its roles in autoinflammatory syndromes and sterile inflammation. Finally, the first inflammasomeindependent engagement of NLRC4 in suppressing melanoma tumor growth is presented. The emerging roles of NLRC4 in various normal and pathological processes demonstrate that there is still plenty to be learned about the NLRC4 mechanism of activation and downstream functions.

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The adaptor ASC has extracellular and 'prionoid' activities that propagate inflammation

Cited by 639 publications

References 52 publications

The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype

The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype

NLRP3, un inflammasome sous contrôle

The NLRC4 inflammasome: The pieces of the puzzle are falling into place

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