The NLRP3 inflammasome in health and disease: the good, the bad and the ugly
P Menu,James E Vince +1 more
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
Citations
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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 recognizes cytosolic dsDNA and forms a caspase-1 activating inflammasome with ASC
Veit Hornung,Veit Hornung,Andrea Ablasser,Andrea Ablasser,Marie Charrel-Dennis,Franz Bauernfeind,Franz Bauernfeind,Gabor Horvath,Daniel R. Caffrey,Eicke Latz,Katherine A. Fitzgerald +10 more
TL;DR: Using mouse and human cells, the PYHIN (pyrin and HIN domain-containing protein) family member absent in melanoma 2 (AIM2) is identified as a receptor for cytosolic DNA, which regulates caspase-1.
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The NALP3 inflammasome is involved in the innate immune response to amyloid-beta.
Annett Halle,Veit Hornung,Gabor C. Petzold,Cameron R. Stewart,Brian G. Monks,Thomas Reinheckel,Katherine A. Fitzgerald,Eicke Latz,Kathryn J. Moore,Douglas T. Golenbock +9 more
TL;DR: The NALP3 inflammasome is identified as a sensor of Aβ in a process involving the phagocytosis of A β and subsequent lysosomal damage and release of cathepsin B.
Journal ArticleDOI
The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance
Bolormaa Vandanmagsar,Yun-Hee Youm,Anthony Ravussin,Jose E. Galgani,Krisztian Stadler,Randall L. Mynatt,Eric Ravussin,Jacqueline M. Stephens,Vishwa Deep Dixit +8 more
TL;DR: It is established that calorie restriction and exercise-mediated weight loss in obese individuals with type 2 diabetes is associated with a reduction in adipose tissue expression of Nlrp3 as well as with decreased inflammation and improved insulin sensitivity, and that the NlrP3 inflammasome senses obesity-associated danger signals and contributes to obesity-induced inflammation and insulin resistance.
Journal ArticleDOI
Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production.
Tatsuya Saitoh,Naonobu Fujita,Myoung Ho Jang,Satoshi Uematsu,Bo-Gie Yang,Takashi Satoh,Hiroko Omori,Takeshi Noda,Naoki Yamamoto,Masaaki Komatsu,Masaaki Komatsu,Masaaki Komatsu,Keiji Tanaka,Taro Kawai,Tohru Tsujimura,Osamu Takeuchi,Tamotsu Yoshimori,Shizuo Akira +17 more
TL;DR: It is shown that Atg16L1 (autophagy-related 16-like 1), which is implicated in Crohn's disease, regulates endotoxin-induced inflammasome activation in mice and is an essential component of the autophagic machinery responsible for control of the endot toxin-induced inflammatory immune response.
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Activation of the NLRP3 inflammasome in dendritic cells induces IL-1β–dependent adaptive immunity against tumors
François Ghiringhelli,Lionel Apetoh,Antoine Tesniere,Antoine Tesniere,Antoine Tesniere,Laetitia Aymeric,Laetitia Aymeric,Laetitia Aymeric,Yuting Ma,Yuting Ma,Yuting Ma,Carla Ortiz,Karim Vermaelen,Theocharis Panaretakis,Theocharis Panaretakis,Theocharis Panaretakis,Grégoire Mignot,Evelyn Ullrich,Evelyn Ullrich,Evelyn Ullrich,Jean-Luc Perfettini,Jean-Luc Perfettini,Jean-Luc Perfettini,Frédéric Schlemmer,Frédéric Schlemmer,Frédéric Schlemmer,Ezgi Tasdemir,Ezgi Tasdemir,Ezgi Tasdemir,Martin Uhl,Pierre Génin,Ahmet Civas,Bernhard Ryffel,Jean Kanellopoulos,Jürg Tschopp,Fabrice Andre,Fabrice Andre,Fabrice Andre,Rosette Lidereau,Nicole McLaughlin,Nicole M. Haynes,Mark J. Smyth,Guido Kroemer,Guido Kroemer,Guido Kroemer,Laurence Zitvogel +45 more
TL;DR: It is shown that dying tumor cells release ATP, which then acts on P2X7 purinergic receptors from DCs and triggers the NOD-like receptor family, pyrin domain containing-3 protein (NLRP3)-dependent caspase-1 activation complex ('inflammasome'), allowing for the secretion of interleukin-1 β (IL-1β).