scholarly journals Inhibition of sterile danger signals, uric acid and ATP, prevents inflammasome activation and protects from alcoholic steatohepatitis in mice

2015 ◽  
Vol 63 (5) ◽  
pp. 1147-1155 ◽  
Author(s):  
Arvin Iracheta-Vellve ◽  
Jan Petrasek ◽  
Abhishek Satishchandran ◽  
Benedek Gyongyosi ◽  
Banishree Saha ◽  
...  
Keyword(s):  
Uric Acid ◽  
Inflammasome Activation ◽  
Danger Signals ◽  
Alcoholic Steatohepatitis

Inflammasomes take the acid test

Inflammasome ◽  
2014 ◽  
Vol 1 (1) ◽  
Author(s):  
David Brough
Keyword(s):  
Extracellular Atp ◽  
Inflammasome Activation ◽  
Danger Signals ◽  
Acid Test

Editorial highlight on Takenouchi et al., ‘Inflammasome activation by danger signals: extracellular ATP and pH.’

scholarly journals Inflammasome Activation Contributes to Interleukin-23 Production in Response to Clostridium difficile

mBio ◽  
2015 ◽  
Vol 6 (1) ◽  
Author(s):  
Carrie A. Cowardin ◽  
Sarah A. Kuehne ◽  
Erica L. Buonomo ◽  
Chelsea S. Marie ◽  
Nigel P. Minton ◽  
...  
Keyword(s):  
Clostridium Difficile ◽  
Disease Severity ◽  
Tissue Damage ◽  
The United States ◽  
Host Cells ◽  
Inflammasome Activation ◽  
Content Type ◽  
Danger Signals ◽  
Interleukin 23 ◽  
Molecular Patterns

ABSTRACT  Clostridium difficileis the most common hospital-acquired pathogen, causing antibiotic-associated diarrhea in over 250,000 patients annually in the United States. Disease is primarily mediated by toxins A and B, which induce potent proinflammatory signaling in host cells and can activate an ASC-containing inflammasome. Recent findings suggest that the intensity of the host response to infection correlates with disease severity. Our lab has identified the proinflammatory cytokine interleukin-23 (IL-23) as a pathogenic mediator during C. difficile infection (CDI). The mechanisms by which C. difficile induces IL-23, however, are not well understood, and the role of toxins A and B in this process is unclear. Here, we show that toxins A and B alone are not sufficient for IL-23 production but synergistically increase the amount of IL-23 produced in response to MyD88-dependent danger signals, including pathogen-associated molecular patterns (PAMPs) and host-derived damage associated molecular patterns (DAMPs). Danger signals also enhanced the secretion of IL-1β in response to toxins A and B, and subsequent IL-1 receptor signaling accounted for the majority of the increase in IL-23 that occurred in the presence of the toxins. Inhibition of inflammasome activation in the presence of extracellular K+likewise decreased IL-23 production. Finally, we found that IL-1β was increased in the serum of patients with CDI, suggesting that this systemic response could influence downstream production of pathogenic IL-23. Identification of the synergy of danger signals with toxins A and B via inflammasome signaling represents a novel finding in the mechanistic understanding of C. difficile-induced inflammation.IMPORTANCEClostridium difficileis among the leading causes of death due to health care-associated infection, and factors determining disease severity are not well understood. C. difficile secretes toxins A and B, which cause inflammation and tissue damage, and recent findings suggest that some of this tissue damage may be due to an inappropriate host immune response. We have found that toxins A and B, in combination with both bacterium- and host-derived danger signals, can induce expression of the proinflammatory cytokines IL-1β and IL-23. Our results demonstrate that IL-1β signaling enhances IL-23 production and could lead to increased pathogenic inflammation during CDI.

scholarly journals Internalization of the Membrane Attack Complex Triggers NLRP3 Inflammasome Activation and IL-1β Secretion in Human Macrophages

2021 ◽  
Vol 12 ◽  
Author(s):  
Ines Diaz-del-Olmo ◽  
Jonathan Worboys ◽  
Fatima Martin-Sanchez ◽  
Anna Gritsenko ◽  
Ashley R. Ambrose ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Pore Formation ◽  
Membrane Attack Complex ◽  
Inflammasome Activation ◽  
Adapter Protein ◽  
Human Macrophages ◽  
Danger Signals ◽  
Nlrp3 Inflammasome Activation ◽  
Golgi Network ◽  
Stimulation Of

Interleukin 1β (IL-1β) plays a major role in inflammation and is secreted by immune cells, such as macrophages, upon recognition of danger signals. Its secretion is regulated by the inflammasome, the assembly of which results in caspase 1 activation leading to gasdermin D (GSDMD) pore formation and IL-1β release. During inflammation, danger signals also activate the complement cascade, resulting in the formation of the membrane attack complex (MAC). Here, we report that stimulation of LPS-primed human macrophages with sub-lytic levels of MAC results in activation of the NOD-like receptor 3 (NLRP3) inflammasome and GSDMD-mediated IL-1β release. The MAC is first internalized into endosomes and then colocalizes with inflammasome components; adapter protein apoptosis associated speck-like protein containing a CARD (ASC) and NLRP3. Pharmacological inhibitors established that MAC-triggered activation of the NLRP3 inflammasome was dependent on MAC endocytosis. Internalization of the MAC also caused dispersion of the trans-Golgi network. Thus, these data uncover a role for the MAC in activating the inflammasome and triggering IL-1β release in human macrophages.

2 IL-1β and Inflammasome Activation in Non-Alcoholic Steatohepatitis is MyD88-Dependent and Amplified by TLR9 Ligands in Mice

2010 ◽  
Vol 138 (5) ◽  
pp. S-773
Author(s):  
Timea Csak ◽  
Michal Ganz ◽  
Angela Dolganiuc ◽  
Karen Kodys ◽  
Gyongyi Szabo
Keyword(s):  
Inflammasome Activation ◽  
Alcoholic Steatohepatitis

scholarly journals Sphingomyelin synthase 1 mediates hepatocyte pyroptosis to trigger non-alcoholic steatohepatitis

Gut ◽  
2020 ◽  
pp. gutjnl-2020-322509
Author(s):  
Eun Hee Koh ◽  
Ji Eun Yoon ◽  
Myoung Seok Ko ◽  
Jaechan Leem ◽  
Ji-Young Yun ◽  
...  
Keyword(s):  
Mouse Models ◽  
Free Cholesterol ◽  
High Cholesterol Diet ◽  
Inflammasome Activation ◽  
Hepatic Expression ◽  
Sphingomyelin Synthase ◽  
Alcoholic Steatohepatitis ◽  
Pyrin Domain ◽  
Hepatocyte Injury

ObjectiveLipotoxic hepatocyte injury is a primary event in non-alcoholic steatohepatitis (NASH), but the mechanisms of lipotoxicity are not fully defined. Sphingolipids and free cholesterol (FC) mediate hepatocyte injury, but their link in NASH has not been explored. We examined the role of free cholesterol and sphingomyelin synthases (SMSs) that generate sphingomyelin (SM) and diacylglycerol (DAG) in hepatocyte pyroptosis, a specific form of programmed cell death associated with inflammasome activation, and NASH.DesignWild-type C57BL/6J mice were fed a high fat and high cholesterol diet (HFHCD) to induce NASH. Hepatic SMS1 and SMS2 expressions were examined in various mouse models including HFHCD-fed mice and patients with NASH. Pyroptosis was estimated by the generation of the gasdermin-D N-terminal fragment. NASH susceptibility and pyroptosis were examined following knockdown of SMS1, protein kinase Cδ (PKCδ), or the NLR family CARD domain-containing protein 4 (NLRC4).ResultsHFHCD increased the hepatic levels of SM and DAG while decreasing the level of phosphatidylcholine. Hepatic expression of Sms1 but not Sms2 was higher in mouse models and patients with NASH. FC in hepatocytes induced Sms1 expression, and Sms1 knockdown prevented HFHCD-induced NASH. DAG produced by SMS1 activated PKCδ and NLRC4 inflammasome to induce hepatocyte pyroptosis. Depletion of Nlrc4 prevented hepatocyte pyroptosis and the development of NASH. Conditioned media from pyroptotic hepatocytes activated the NOD-like receptor family pyrin domain containing 3 inflammasome (NLRP3) in Kupffer cells, but Nlrp3 knockout mice were not protected against HFHCD-induced hepatocyte pyroptosis.ConclusionSMS1 mediates hepatocyte pyroptosis through a novel DAG-PKCδ-NLRC4 axis and holds promise as a therapeutic target for NASH.

Tudca Protects against Endoplasmic Reticulum Stress-Induced Inflammasome Activation and Hepatocyte Death in Non-Alcoholic Steatohepatitis

2016 ◽  
Vol 64 (2) ◽  
pp. S676
Author(s):  
C. Lebeaupin ◽  
E. Proics ◽  
C.-H.D. de Bieville ◽  
D. Rousseau ◽  
S. Bonnafous ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Inflammasome Activation ◽  
Alcoholic Steatohepatitis ◽  
Hepatocyte Death
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