Adenovirus membrane penetration activates the NLRP3 inflammasome.
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TLDR
Using lentivirus-expressed short hairpin RNA (shRNA) and competitive inhibitors, it is shown that Ad-induced IL-1β release is dependent upon Toll-like receptor 9 (TLR9) sensing of the Ad5 double-stranded DNA (dsDNA) genome in human cell lines and primary monocyte-derived macrophage but not in mouse macrophages.Abstract:
Adenovirus type 5 (Ad5) infection of macrophages results in rapid secretion of interleukin-1β (IL-1β) and is dependent on the inflammasome components NLRP3 and ASC and the catalytic activity of caspase-1. Using lentivirus-expressed short hairpin RNA (shRNA) and competitive inhibitors, we show that Ad-induced IL-1β release is dependent upon Toll-like receptor 9 (TLR9) sensing of the Ad5 double-stranded DNA (dsDNA) genome in human cell lines and primary monocyte-derived macrophages but not in mouse macrophages. Additionally, a temperature-sensitive mutant of Ad5 unable to penetrate endosomal membranes, ts1, is unable to induce IL-1β release in TLR2-primed THP-1 cells, suggesting that penetration of endosomal membranes is required for IL-1β release. Disruption of lysosomal membranes and the release of cathepsin B into the cytoplasm are required for Ad-induced NLRP3 activation. Ad5 cell entry also induces reactive oxygen species (ROS) production, and inhibitors of ROS prevent Ad-induced IL-1β release. Ad5 activation of NLRP3 also induces necrotic cell death, resulting in the release of the proinflammatory molecule HMGB1. This work further defines the mechanisms of virally induced inflammasome activation.read more
Citations
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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.
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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.
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Recent advances in the mechanisms of NLRP3 inflammasome activation and its inhibitors.
TL;DR: Current understanding of the regulatory mechanisms of NLRP3 inflammasome activation as well as inhibitors that specifically and directly targetNLRP3 are summarized.
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HMGB1 in Health and Disease
Rui Kang,Ruochan Chen,Qiuhong Zhang,Wen Hou,Sha Wu,Lizhi Cao,Jin Huang,Yan Yu,Xue Gong Fan,Zhengwen Yan,Zhengwen Yan,Xiaofang Sun,Haichao Wang,Qingde Wang,Allan Tsung,Timothy R. Billiar,Herbert J. Zeh,Michael T. Lotze,Daolin Tang +18 more
TL;DR: High-mobility group box 1 (HMGB1), the most abundant and well-studied HMG protein, senses and coordinates the cellular stress response and plays a critical role not only inside of the cell as a DNA chaperone, chromosome guardian, autophagy sustainer, and protector from apoptotic cell death, but also outside thecell as the prototypic damage associated molecular pattern molecule (DAMP).
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Adenovirus Vectors for Gene Therapy, Vaccination and Cancer Gene Therapy
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TL;DR: Many clinical trials indicate that replication-defective and replication-competent adenovirus vectors are safe and have therapeutic activity, and these vectors are employed for cancer gene therapy.
References
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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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The Inflammasomes: Guardians of the Body
TL;DR: The role of NLRs, and in particular the inflammasomes, in the recognition of microbial and danger components and the role they play in health and disease are discussed.
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Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression.
Franz Bauernfeind,Gabor Horvath,Andrea Stutz,Emad S. Alnemri,Kelly S. MacDonald,David P. Speert,Teresa Fernandes-Alnemri,Jianghong Wu,Brian G. Monks,Katherine A. Fitzgerald,Veit Hornung,Eicke Latz +11 more
TL;DR: It is shown that cell priming through multiple signaling receptors induces NLRP3 expression, which is identified to be a critical checkpoint for NLRP2 activation and signals provided by NF-κB activators are necessary but not sufficient forNLRP3 activation.
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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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AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA
TL;DR: This study identifies AIM2 as an important inflammasome component that senses potentially dangerous cytoplasmic DNA, leading to activation of the ASC pyroptosome and caspase-1.