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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Innate immune detection of the type III secretion apparatus through the NLRC4 inflammasome
Edward A. Miao,Dat P. Mao,Natalya Yudkovsky,Richard Bonneau,Cynthia G. Lorang,Sarah E. Warren,Sarah E. Warren,Irina A. Leaf,Alan Aderem +8 more
TL;DR: The detection of a conserved component of the T3ss apparatus enables innate immune responses to virulent bacteria through a single pathway, a strategy that is divergent from that used by plants in which multiple NB-LRR proteins are used to detect T3SS effectors or their effects on cells as discussed by the authors.
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The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer
Irving C. Allen,Erin McElvania TeKippe,Rita Marie T Woodford,Joshua M. Uronis,Eda K. Holl,Arlin B. Rogers,Hans H Herfarth,Christian Jobin,Jenny P.-Y. Ting +8 more
TL;DR: Bone marrow reconstitution experiments show that Nlrp3 gene expression and function in hematopoietic cells, rather than intestinal epithelial cells or stromal cells, is responsible for protection against increased tumorigenesis, suggesting that the inflammasome functions as an attenuator of colitis and CAC.