scholarly journals Recent insights into the regulatory networks of NLRP3 inflammasome activation

2020 ◽  
Vol 133 (23) ◽  
pp. jcs248344 ◽  
Author(s):  
Alexander N. R. Weber ◽  
Zsófia A. Bittner ◽  
Sangeetha Shankar ◽  
Xiao Liu ◽  
Tzu-Hsuan Chang ◽  
...  
Keyword(s):  
Cell Death ◽  
Nlrp3 Inflammasome ◽  
Regulatory Networks ◽  
Proteolytic Processing ◽  
Inflammasome Activation ◽  
Post Translational Modification ◽  
Cell Death Pathways ◽  
Open Questions ◽  
Cellular Machinery ◽  
Death Effector

ABSTRACTThe NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome is a fascinating cellular machinery endowed with the capacity for rapid proteolytic processing of the pro-inflammatory cytokine IL-1β and the cell death effector gasdermin D (GSDMD). Although its activity is essential to fight infection and support tissue homeostasis, the inflammasome complex, which consists of the danger sensor NLRP3, the adaptor apoptosis-associated speck-like protein containing a CARD (ASC; also known as PYCARD), caspase-1 and probably other regulatory proteins, also bears considerable potential for detrimental inflammation, as observed in human conditions such as gout, heart attack, stroke and Alzheimer's disease. Thus, multi-layered regulatory networks are required to ensure the fine balance between rapid responsiveness versus erroneous activation (sufficient and temporally restricted versus excessive and chronic activity) of the inflammasome. These involve multiple activation, secretion and cell death pathways, as well as modulation of the subcellular localization of NLRP3, and its structure and activity, owing to post-translational modification by other cellular proteins. Here, we discuss the exciting progress that has recently been made in deciphering the regulation of the NLRP3 inflammasome. Additionally, we highlight open questions and describe areas of research that warrant further exploration to obtain a more comprehensive molecular and cellular understanding of the NLRP3 inflammasome.

scholarly journals Plasma-borne indicators of inflammasome activity in Parkinson’s disease patients

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Faith L. Anderson ◽  
Katharine M. von Herrmann ◽  
Angeline S. Andrew ◽  
Yuliya I. Kuras ◽  
Alison L. Young ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Death ◽  
Nlrp3 Inflammasome ◽  
Neurodegenerative Disorder ◽  
Early Stage ◽  
Inflammasome Activation ◽  
Membrane Pore ◽  
Related Proteins ◽  
Inflammasome Activity

AbstractParkinson’s disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms and loss of dopaminergic neurons of the substantia nigra. Inflammation and cell death are recognized aspects of PD suggesting that strategies to monitor and modify these processes may improve the management of the disease. Inflammasomes are pro-inflammatory intracellular pattern recognition complexes that couple these processes. The NLRP3 inflammasome responds to sterile triggers to initiate pro-inflammatory processes characterized by maturation of inflammatory cytokines, cytoplasmic membrane pore formation, vesicular shedding, and if unresolved, pyroptotic cell death. Histologic analysis of tissues from PD patients and individuals with nigral cell loss but no diagnosis of PD identified elevated expression of inflammasome-related proteins and activation-related “speck” formation in degenerating mesencephalic tissues compared with controls. Based on previous reports of circulating inflammasome proteins in patients suffering from heritable syndromes caused by hyper-activation of the NLRP3 inflammasome, we evaluated PD patient plasma for evidence of inflammasome activity. Multiple circulating inflammasome proteins were detected almost exclusively in extracellular vesicles indicative of ongoing inflammasome activation and pyroptosis. Analysis of plasma obtained from a multi-center cohort identified elevated plasma-borne NLRP3 associated with PD status. Our findings are consistent with others indicating inflammasome activity in neurodegenerative disorders. Findings suggest mesencephalic inflammasome protein expression as a histopathologic marker of early-stage nigral degeneration and suggest plasma-borne inflammasome-related proteins as a potentially useful class of biomarkers for patient stratification and the detection and monitoring of inflammation in PD.

scholarly journals The Zα2 domain of ZBP1 is a molecular switch regulating influenza-induced PANoptosis and perinatal lethality during development

2020 ◽  
Vol 295 (24) ◽  
pp. 8325-8330 ◽  
Author(s):  
Sannula Kesavardhana ◽  
R. K. Subbarao Malireddi ◽  
Amanda R. Burton ◽  
Shaina N. Porter ◽  
Peter Vogel ◽  
...  
Keyword(s):  
Cell Death ◽  
Nucleic Acids ◽  
Influenza A Virus ◽  
Nlrp3 Inflammasome ◽  
Influenza A ◽  
Defense Responses ◽  
Innate Immune ◽  
Inflammasome Activation ◽  
Perinatal Lethality

Z-DNA-binding protein 1 (ZBP1) is an innate immune sensor of nucleic acids that regulates host defense responses and development. ZBP1 activation triggers inflammation and pyroptosis, necroptosis, and apoptosis (PANoptosis) by activating receptor-interacting Ser/Thr kinase 3 (RIPK3), caspase-8, and the NLRP3 inflammasome. ZBP1 is unique among innate immune sensors because of its N-terminal Zα1 and Zα2 domains, which bind to nucleic acids in the Z-conformation. However, the specific role of these Zα domains in orchestrating ZBP1 activation and subsequent inflammation and cell death is not clear. Here we generated Zbp1ΔZα2/ΔZα2 mice that express ZBP1 lacking the Zα2 domain and demonstrate that this domain is critical for influenza A virus–induced PANoptosis and underlies perinatal lethality in mice in which the RIP homotypic interaction motif domain of RIPK1 has been mutated (Ripk1mRHIM/mRHIM). Deletion of the Zα2 domain in ZBP1 abolished influenza A virus–induced PANoptosis and NLRP3 inflammasome activation. Furthermore, deletion of the Zα2 domain of ZBP1 was sufficient to rescue Ripk1mRHIM/mRHIM mice from perinatal lethality caused by ZBP1-driven cell death and inflammation. Our findings identify the essential role of the Zα2 domain of ZBP1 in several physiological functions and establish a link between Z-RNA sensing via the Zα2 domain and promotion of influenza-induced PANoptosis and perinatal lethality.

scholarly journals Inflammation in nonischemic heart disease: initiation by cardiomyocyte CaMKII and NLRP3 inflammasome signaling

2019 ◽  
Vol 317 (5) ◽  
pp. H877-H890 ◽  
Author(s):  
Takeshi Suetomi ◽  
Shigeki Miyamoto ◽  
Joan Heller Brown
Keyword(s):  
Cell Death ◽  
Heart Disease ◽  
Nlrp3 Inflammasome ◽  
Immune Cell ◽  
Cell Damage ◽  
Nuclear Factor Κb ◽  
Inflammasome Activation ◽  
Monocyte Chemoattractant Protein 1 ◽  
Pyrin Domain ◽  
Cytokines And Chemokines

There is substantial evidence that chronic heart failure in humans and in animal models is associated with inflammation. Ischemic interventions such as myocardial infarction lead to necrotic cell death and release of damage associated molecular patterns, factors that signal cell damage and induce expression of proinflammatory chemokines and cytokines. It has recently become evident that nonischemic interventions are also associated with increases in inflammatory genes and immune cell accumulation in the heart and that these contribute to fibrosis and ventricular dysfunction. How proinflammatory responses are elicited in nonischemic heart disease which is not, at least initially, associated with cell death is a critical unanswered question. In this review we provide evidence supporting the hypothesis that cardiomyocytes are an initiating site of inflammatory gene expression in response to nonischemic stress. Furthermore we discuss the role of the multifunctional Ca2+/calmodulin-regulated kinase, CaMKIIδ, as a transducer of stress signals to nuclear factor-κB activation, expression of proinflammatory cytokines and chemokines, and priming and activation of the NOD-like pyrin domain-containing protein 3 (NLRP3) inflammasome in cardiomyocytes. We summarize recent evidence that subsequent macrophage recruitment, fibrosis and contractile dysfunction induced by angiotensin II infusion or transverse aortic constriction are ameliorated by blockade of CaMKII, of monocyte chemoattractant protein-1/C-C chemokine receptor type 2 signaling, or of NLRP3 inflammasome activation.

Lysosomes in programmed cell death pathways: from initiators to amplifiers

2017 ◽  
Vol 398 (3) ◽  
pp. 289-301 ◽  
Author(s):  
Nežka Kavčič ◽  
Katarina Pegan ◽  
Boris Turk
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Membrane Permeabilization ◽  
Lysosomal Membrane ◽  
Inflammasome Activation ◽  
Biological Macromolecules ◽  
Lysosomal Hydrolases ◽  
Lysosomal Membrane Permeabilization ◽  
Cell Death Pathways ◽  
Major Attention

Abstract Lysosome is the central organelle for intracellular degradation of biological macromolecules and organelles. The material destined for degradation enters the lysosomes primarily via endocytosis, autophagy and phagocytosis, and is degraded through the concerted action of more than 50 lysosomal hydrolases. However, lysosomes are also linked with numerous other processes, including cell death, inflammasome activation and immune response, as well as with lysosomal secretion and cholesterol recycling. Among them programmed cell death pathways including apoptosis have received major attention. In most of these pathways, cell death was accompanied by lysosomal membrane permeabilization and release of lysosomal constituents with an involvement of lysosomal hydrolases, including the cathepsins. However, it is less clear, whether lysosomal membrane permeabilization is really critical for the initiation of cell death programme(s). Therefore, the role of lysosomal membrane permeabilization in various programmed cell death pathways is reviewed, as well as the mechanisms leading to it.

scholarly journals Hydrogen Peroxide Is Crucial for NLRP3 Inflammasome-Mediated IL-1β Production and Cell Death in Pneumococcal Infections of Bronchial Epithelial Cells

2021 ◽  
pp. 1-15
Author(s):  
Surabhi Surabhi ◽  
Lana H. Jachmann ◽  
Patience Shumba ◽  
Gerhard Burchhardt ◽  
Sven Hammerschmidt ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Cell Death ◽  
Epithelial Cells ◽  
Respiratory Tract ◽  
Nlrp3 Inflammasome ◽  
Lower Respiratory Tract ◽  
Pneumococcal Infections ◽  
Cell Death Pathways ◽  
Epithelial Cell Death

Epithelial cells play a crucial role in detection of the pathogens as well as in initiation of the host immune response<i>. Streptococcus pneumoniae</i> (pneumococcus) is a typical colonizer of the human nasopharynx, which can disseminate to the lower respiratory tract and subsequently cause severe invasive diseases such as pneumonia, sepsis, and meningitis. Hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) is produced by pneumococci as a product of the pyruvate oxidase SpxB. However, its role as a virulence determinant in pneumococcal infections of the lower respiratory tract is not well understood. In this study, we investigated the role of pneumococcal-derived H<sub>2</sub>O<sub>2</sub> in initiating epithelial cell death by analyzing the interplay between 2 key cell death pathways, namely, apoptosis and pyroptosis. We demonstrate that H<sub>2</sub>O<sub>2</sub> primes as well as activates the NLRP3 inflammasome and thereby mediates IL-1β production and release. Furthermore, we show that pneumococcal H<sub>2</sub>O<sub>2</sub> causes cell death via the activation of both apoptotic as well as pyroptotic pathways which are mediated by the activation of caspase-3/7 and caspase-1, respectively. However, H<sub>2</sub>O<sub>2</sub>-mediated IL-1β release itself occurs mainly via apoptosis.

scholarly journals IRF8 Regulates Gram-Negative Bacteria–Mediated NLRP3 Inflammasome Activation and Cell Death

2020 ◽  
Vol 204 (9) ◽  
pp. 2514-2522 ◽  
Author(s):  
Rajendra Karki ◽  
Ein Lee ◽  
Bhesh R. Sharma ◽  
Balaji Banoth ◽  
Thirumala-Devi Kanneganti
Keyword(s):  
Cell Death ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Nlrp3 Inflammasome Activation

scholarly journals ZBP1: A STARGᐰTE to decode the biology of Z-nucleic acids in disease

2020 ◽  
Vol 217 (7) ◽  
Author(s):  
Sannula Kesavardhana ◽  
Thirumala-Devi Kanneganti
Keyword(s):  
Cell Death ◽  
Nucleic Acids ◽  
Inflammatory Disease ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Specific Ligand

ZBP1 triggers NLRP3 inflammasome activation/pyroptosis, apoptosis, and necroptosis; the specific ligand for ZBP1 activation remains ambiguous. Recent studies, including Devos et al. in this issue of JEM (https://doi.org/10.1084/jem.20191913), collectively suggest that ZBP1 sensing Z-nucleic acids is critical for cell death/inflammatory disease.

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