Inflammasome activation causes dual recruitment of NLRC4 and NLRP3 to the same macromolecular complex

Man, Si Ming; Hopkins, Lee; Nugent, Eileen; Cox, Susan; Glück, Ivo M.; Tourlomousis, Panagiotis; Wright, John A.; Cicuta, Pietro; Monie, Tom P.; Bryant, Clare E.

doi:10.1073/pnas.1402911111

Cited by 311 publications

(362 citation statements)

References 37 publications

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“…Experiments were next performed to determine whether the regulation of caspase-8 was downstream of the Nlrp3 inflammasome. The activation of the Nlrp3 inflammasome using the canonical agonist nigericin in bone marrow-derived macrophages (BMDM) results in the activation of both caspase-1 and caspase-8 as previously reported 4,13 (Supplementary Figure S5). In the absence of caspase-1 or caspase-11, caspase-8 activation by nigericin is maintained confirming that caspase-8 is a downstream effector of the Nlrp3 inflammasome.…”

Section: Resultssupporting

confidence: 72%

“…6,10 Initiation of mitochondrial apoptosis also releases SMAC/DIABLO, which inhibits XIAP and enables caspase-3 to further activate caspase-8. 11 Caspase-8 is also activated downstream of the NLRP3, AIM2 and NLRC4 inflammasomes in response to canonical triggers in macrophages 4,[12][13][14] or downstream of Dectin-1 in dendritic cells. [15][16][17] The activation of caspase-8 in leukocytes requires ASC and regulates the non-canonical maturation of IL-1β.…”

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confidence: 99%

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NLRP3 regulates a non-canonical platform for caspase-8 activation during epithelial cell apoptosis

et al. 2016

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Nod-like receptor, pyrin containing 3 (NLRP3) is characterized primarily as a canonical caspase-1 activating inflammasome in macrophages. NLRP3 is also expressed in the epithelium of the kidney and gut; however, its function remains largely undefined. Primary mouse tubular epithelial cells (TEC) lacking Nlrp3 displayed reduced apoptosis downstream of the tumor necrosis factor (TNF) receptor and CD95. TECs were identified as type II apoptotic cells that activated caspase-8, tBid and mitochondrial apoptosis via caspase-9, responses that were reduced in Nlrp3 − / − cells. The activation of caspase-8 during extrinsic apoptosis induced by TNFα/cycloheximide (TNFα/CHX) was dependent on adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC) and completely independent of caspase-1 or caspase-11. TECs and primary human proximal tubular epithelial cells (HPTC) did not activate a canonical inflammasome, caspase-1, or IL-1β secretion in response to TNFα/CHX or NLRP3-dependent triggers, such as ATP or nigericin. In cell fractionation studies and by confocal microscopy, NLRP3 colocalized with ASC and caspase-8 in speck-like complexes at the mitochondria during apoptosis. The formation of NLRP3/ASC/caspase-8 specks in response to TNFα/ CHX was downstream of TNFR signaling and dependent on potassium efflux. Epithelial ASC specks were present in enteroids undergoing apoptosis and in the injured tubules of wild-type but not Nlrp3 − / − or ASC − / − mice following ureteric unilateral obstruction in vivo. These data show that NLRP3 and ASC form a conserved non-canonical platform for caspase-8 activation, independent of the inflammasome that regulates apoptosis within epithelial cells.

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Section: Resultssupporting

confidence: 72%

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confidence: 99%

NLRP3 regulates a non-canonical platform for caspase-8 activation during epithelial cell apoptosis

et al. 2016

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“…Super-resolution fluorescence microscopy revealed that caspase-1 makes the core, surrounded by NLRP3 and NLRC4 rings, while ASC positions into a large external ring. Colocalization of NLRP3 and NLRC4 was only partial, with NLRP3 composing a ring with lower diameter than NLRC4 [64]. Interestingly, while hypoosmotic conditions activate the NLRP3 inflammasome due to K + efflux and Ca 2+ influx [65], hyperosmotic conditions signal through NLRP3 and NLRC4, independently of K + efflux (Fig.…”

Section: The Role Of Asc In Cytokine Maturation and Pyroptosismentioning

confidence: 88%

“…NLRC4 is able to co-immunoprecipitate with NLRP3 [63] and there are more indications that various NLRs can be found in the same complex. Both receptors were recruited to the same macromolecular complex upon S. Typhimurium infection [64]. Super-resolution fluorescence microscopy revealed that caspase-1 makes the core, surrounded by NLRP3 and NLRC4 rings, while ASC positions into a large external ring.…”

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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“…To catalyze the proteolytic cleavage of pro-interleukin (IL)-1β and pro-IL-18, which results into pyroptosis, NLRs and ALRs engage caspase-1, through the adapter protein apoptosis-associated specklike protein, containing a CARD (ASC), (Man and Kanneganti, 2015). To become activated AIM2 or NLRP3 require the polymerization of the N terminal pyridine domain (PYD) of ASC (Lu et al, 2014;Cai et al, 2014), which, as final step, leads to the formation of a single and distinct inflammasome speck that could be detected in primary macrophages and dendritic cells (DCs) (Man et al, 2014;2015a;Belhocine and Monack, 2012). Recently Bakele and colleagues showed that human neutrophils also express the key components of the NLRP3 and AIM2 inflammasome machinery in different intra-cellular compartments and they are capable to release key cytokines.…”

Section: Introductionmentioning

confidence: 99%

The Duality of AIM2 Inflammasome: A Focus on its Role in Autoimmunity and Skin Diseases

Canavese¹

2016

American Journal of Pharmacology and Toxicology

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Understanding the inflammasome biology is one of the most exciting challenges in immuno-pharmacology. The role of the inflammasomes has been recognized in the host defense mechanism against invading pathogens and in the development of several conditions, such as cancer, auto-inflammatory, autoimmune, metabolic and neurodegenerative disorders. DNA recognition by the cells is a crucial immunological step leading to the initiation of an innate immune response. Absent in Melanoma 2 (AIM2) is a cytoplasmic sensor that perceives double-stranded DNA of microbial or host origin. Once the DNA is bound, AIM2 assembles a multiprotein complex named inflammasome, which drives pyroptosis and proteolytic cleavage of pro-IL-1β and pro-IL-18 pro-inflammatory cytokines, leading to a protective inflammasome-mediated host response. However, improper recognition of self-DNA by AIM2 triggers deleterious inflammatory responses, leading to systemic inflammation and several pathological conditions. Therefore, understanding the mechanisms of AIM2-inflammasome-mediated inflammation will provide an essential knowledge base to develop new successful therapeutic strategies to cure the outlined pathologies in which AIM2-inflammasome activation plays a key role, as well as to guide clinical practice. This mini-review provides an overview on the latest research findings on AIM2 inflammasome, with particular focus on its role in autoimmunity and skin disorders. An update on its therapeutic implications has also been documented.

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Inflammasome activation causes dual recruitment of NLRC4 and NLRP3 to the same macromolecular complex

Cited by 311 publications

References 37 publications

NLRP3 regulates a non-canonical platform for caspase-8 activation during epithelial cell apoptosis

NLRP3 regulates a non-canonical platform for caspase-8 activation during epithelial cell apoptosis

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

The Duality of AIM2 Inflammasome: A Focus on its Role in Autoimmunity and Skin Diseases

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