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
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TLDR
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.Abstract:
The innate immune system senses nucleic acids by germline-encoded pattern recognition receptors. RNA is sensed by Toll-like receptor members TLR3, TLR7 and TLR8, or by the RNA helicases RIG-I (also known as DDX58) and MDA-5 (IFIH1). Little is known about sensors for cytoplasmic DNA that trigger antiviral and/or inflammatory responses. The best characterized of these responses involves activation of the TANK-binding kinase (TBK1)-interferon regulatory factor 3 (IRF3) signalling axis to trigger transcriptional induction of type I interferon genes. A second, less well-defined pathway leads to the activation of an 'inflammasome' that, via caspase-1, controls the catalytic cleavage of the pro-forms of the cytokines IL1beta and IL18 (refs 6, 7). Using mouse and human cells, here we identify the PYHIN (pyrin and HIN domain-containing protein) family member absent in melanoma 2 (AIM2) as a receptor for cytosolic DNA, which regulates caspase-1. The HIN200 domain of AIM2 binds to DNA, whereas the pyrin domain (but not that of the other PYHIN family members) associates with the adaptor molecule ASC (apoptosis-associated speck-like protein containing a caspase activation and recruitment domain) to activate both NF-kappaB and caspase-1. Knockdown of Aim2 abrogates caspase-1 activation in response to cytoplasmic double-stranded DNA and the double-stranded DNA vaccinia virus. Collectively, these observations identify AIM2 as a new receptor for cytoplasmic DNA, which forms an inflammasome with the ligand and ASC to activate caspase-1.read more
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NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals
Peter Duewell,Hajime Kono,Katey J. Rayner,Katey J. Rayner,Cherilyn M. Sirois,Gregory I. Vladimer,Franz Bauernfeind,George S. Abela,Luigi Franchi,Guillermo Gabriel Nuñez,Max Schnurr,Terje Espevik,Egil Lien,Katherine A. Fitzgerald,Kenneth L. Rock,Kathryn J. Moore,Kathryn J. Moore,Samuel D. Wright,Veit Hornung,Eicke Latz,Eicke Latz +20 more
TL;DR: It is shown that cholesterol crystals activate the NLRP3 inflammasome in phagocytes in vitro in a process that involves phagolysosomal damage and that crystalline cholesterol acts as an endogenous danger signal and its deposition in arteries or elsewhere is an early cause rather than a late consequence of inflammation.
Journal ArticleDOI
Pathogen Recognition and Inflammatory Signaling in Innate Immune Defenses
TL;DR: This review presents current knowledge on pathogen recognition through different families of PRRs and the increasingly complex signaling pathways responsible for activation of an inflammatory and antimicrobial response and medical implications are discussed.
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Sterile inflammation: sensing and reacting to damage
Grace Y. Chen,Gabriel Núñez +1 more
TL;DR: The triggers and receptor pathways that result in sterile inflammation and its impact on human health are reviewed.
Journal ArticleDOI
Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling
Nobuhiko Kayagaki,Irma B. Stowe,Bettina L. Lee,Karen O'Rourke,Keith R. Anderson,Søren Warming,Trinna L. Cuellar,Benjamin Haley,Merone Roose-Girma,Qui T. Phung,Peter Liu,Jennie R. Lill,Hong Li,Jiansheng Wu,Sarah K. Kummerfeld,Juan Zhang,Wyne P. Lee,Scott J. Snipas,Guy S. Salvesen,Lucy X. Morris,Linda Fitzgerald,Yafei Zhang,Edward M. Bertram,Christopher C. Goodnow,Christopher C. Goodnow,Christopher C. Goodnow,Vishva M. Dixit +26 more
TL;DR: It is shown that gasdermin D is essential for caspase-11-dependent pyroptosis and interleukin-1β maturation and a key mediator of the host response against Gram-negative bacteria.
Journal ArticleDOI
Inflammasomes: mechanism of action, role in disease, and therapeutics
TL;DR: Increasing evidence in mouse models strongly implicates an involvement of the inflammasome in the initiation or progression of diseases with a high impact on public health, such as metabolic disorders and neurodegenerative diseases.
References
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Journal ArticleDOI
MUSCLE: multiple sequence alignment with high accuracy and high throughput
TL;DR: MUSCLE is a new computer program for creating multiple alignments of protein sequences that includes fast distance estimation using kmer counting, progressive alignment using a new profile function the authors call the log-expectation score, and refinement using tree-dependent restricted partitioning.
Journal ArticleDOI
Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization
Veit Hornung,Franz Bauernfeind,Annett Halle,Eivind O. Samstad,Eivind O. Samstad,Hajime Kono,Kenneth L. Rock,Katherine A. Fitzgerald,Eicke Latz,Eicke Latz +9 more
TL;DR: It is demonstrated that silica and aluminum salt crystals activated inflammasomes formed by the cytoplasmic receptor NALP3, which senses lysosomal damage as an endogenous 'danger' signal.
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DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response
Akinori Takaoka,ZhiChao Wang,Myoung Kwon Choi,Hideyuki Yanai,Hideo Negishi,Tatsuma Ban,Yan Lu,Makoto Miyagishi,Tatsuhiko Kodama,Kenya Honda,Yusuke Ohba,Tadatsugu Taniguchi +11 more
TL;DR: The artificial expression of otherwise IFN-inducible DAI (DLM-1/ZBP1) in mouse fibroblasts selectively enhances the DNA-mediated induction of type I IFN and other genes involved in innate immunity, and may offer new insight into the signalling mechanisms underlying DNA-associated antimicrobial immunity and autoimmune disorders.
Journal ArticleDOI
Intracellular pattern recognition receptors in the host response
TL;DR: It is apparent that Toll-like receptors, a class of membrane receptors that sense extracellular microbes and trigger anti-pathogen signalling cascades, are likely to have critical roles in health and disease.
Journal ArticleDOI
Recognition of Cytosolic DNA Activates an IRF3-Dependent Innate Immune Response
TL;DR: Evidence is presented that cytosolic DNA activates a potent type I interferon response to the invasive bacterium Listeria monocytogenes, and a unique but overlapping gene-expression program activated by cytOSolic DNA compared to TLR9- and RIG-I/MDA5-dependent responses.