The NLRP3 inflammasome in health and disease: the good, the bad and the ugly
P Menu,James E Vince +1 more
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TLDR
Recently, inflammasome function has been implicated in more common human conditions, which raises the possibility that anti‐IL‐1 therapeutics may have broader applications than anticipated previously, and may be utilized across diverse disease states that are linked insidiously through unwanted or heightened inflammaome activity.Abstract:
While interleukin (IL)-1β plays an important role in combating the invading pathogen as part of the innate immune response, its dysregulation is responsible for a number of autoinflammatory disorders. Large IL-1β activating platforms, known as inflammasomes, can assemble in response to the detection of endogenous host and pathogen-associated danger molecules. Formation of these protein complexes results in the autocatalysis and activation of caspase-1, which processes precursor IL-1β into its secreted biologically active form. Inflammasome and IL-1β activity is required to efficiently control viral, bacterial and fungal pathogen infections. Conversely, excess IL-1β activity contributes to human disease, and its inhibition has proved therapeutically beneficial in the treatment of a spectrum of serious, yet relatively rare, heritable inflammasomopathies. Recently, inflammasome function has been implicated in more common human conditions, such as gout, type II diabetes and cancer. This raises the possibility that anti-IL-1 therapeutics may have broader applications than anticipated previously, and may be utilized across diverse disease states that are linked insidiously through unwanted or heightened inflammasome activity.read more
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Journal ArticleDOI
The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation.
TL;DR: Current understanding of the mechanisms ofNLRP3 inflammasome activation by multiple signaling events, and its regulation by post-translational modifications and interacting partners of NLRP3 are summarized.
Journal ArticleDOI
Molecular mechanisms regulating NLRP3 inflammasome activation.
TL;DR: The NLRP3 inflammasome is linked with various human autoinflammatory and autoimmune diseases and may be a promising target for anti-inflammatory therapies, according to current understanding of the mechanisms by which it is activated in the cytosol.
Journal ArticleDOI
Pyroptosis versus necroptosis: similarities, differences, and crosstalk
TL;DR: Recent discoveries that have advanced understanding on the primary functions of pyroptosis and necroptosis are discussed, including evidence for the specific cytokines and DAMPs responsible for driving inflammation.
Journal ArticleDOI
RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL
Kate E. Lawlor,Nufail Khan,Alison L Mildenhall,Motti Gerlic,Ben A. Croker,Akshay A. D’Cruz,Cathrine Hall,Sukhdeep Kaur. Spall,Holly Anderton,Seth L. Masters,Maryam Rashidi,Ian P. Wicks,Warren S. Alexander,Yasuhiro Mitsuuchi,Christopher A. Benetatos,Stephen M. Condon,W. Wei-Lynn Wong,John Silke,David L. Vaux,James E Vince +19 more
TL;DR: It is shown that following LPS treatment, or LPS-induced necroptosis, the TLR adaptor protein TRIF and inhibitor of apoptosis proteins (IAPs: X-linked IAP, cellular IAP1 and IAP2) regulate RIPK3 and MLKL ubiquitylation, and RIPK 3 can promote NLRP3 inflammasome and IL-1β inflammatory responses independent ofMLKL and necroPTotic cell death.
References
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AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA
TL;DR: In this paper, an interferon-inducible HIN-200 family member, AIM2, was identified as an important inflammasome component that senses potentially dangerous cytoplasmic DNA, leading to activation of the ASC pyroptosome and caspase-1.
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Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration.
Virginie Pétrilli,Papin S,Catherine Dostert,Annick Mayor,Fabio Martinon,Fabio Martinon,J. Tschopp +6 more
TL;DR: Evidence is provided that activation of NALP3, but not of the IPAF inflammasome, is blocked by inhibiting K+ efflux from cells, suggesting that low intracellular K+ may be the least common trigger of NalP-inflammasomes activation.
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The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses.
Vijay A. K. Rathinam,Zhaozhao Jiang,Stephen N. Waggoner,Shrutie Sharma,Leah E. Cole,Lisa Waggoner,Sivapriya Kailasan Vanaja,Brian G. Monks,Sandhya Ganesan,Eicke Latz,Veit Hornung,Stefanie N. Vogel,Eva Szomolanyi-Tsuda,Katherine A. Fitzgerald +13 more
TL;DR: A central role is identified in regulating caspase-1-dependent maturation of IL-1β and IL-18, as well as pyroptosis, in response to synthetic double-stranded DNA, demonstrating the importance of AIM2 in the sensing of both bacterial and viral pathogens and in triggering innate immunity.
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Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes
Seth L. Masters,Aisling Dunne,Shoba L. Subramanian,Rebecca L. Hull,Gillian M. Tannahill,Fiona A. Sharp,Christine Becker,Luigi Franchi,Eiji Yoshihara,Zhe Chen,Niamh Mullooly,Lisa A. Mielke,James Harris,Rebecca C. Coll,Kingston H. G. Mills,K. Hun Mok,Philip Newsholme,Gabriel Núñez,Junji Yodoi,Steven E. Kahn,Ed C. Lavelle,Luke A. J. O'Neill +21 more
TL;DR: It is shown that oligomers of islet amyloid polypeptide (IAPP), a protein that formsAmyloid deposits in the pancreas during type 2 diabetes, triggered the NLRP3 inflammasome and generated mature IL-1β.
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Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1β in salmonella-infected macrophages
Luigi Franchi,Amal O. Amer,Mathilde Body-Malapel,Thirumala-Devi Kanneganti,Nesrin Özören,Rajesh Jagirdar,Naohiro Inohara,Peter Vandenabeele,John Bertin,Anthony J. Coyle,Anthony J. Coyle,Ethan P. Grant,Gabriel Núñez +12 more
TL;DR: The authors showed that salmonella-infected and lipopolysaccharide-tolerant macrophages were deficient in activation of caspase-1 and in interleukin 1beta secretion, although transcription factor NF-kappaB-dependent production of the chemokine MCP-1 was unimpaired.