Structure, Activation and Regulation of NLRP3 and AIM2 Inflammasomes

The inflammasome is a three-component (sensor, adaptor, and effector) filamentous signaling platform that shields from multiple pathogenic infections by stimulating the proteolytical maturation of proinflammatory cytokines and pyroptotic cell death. The signaling process initiates with the detection of endogenous and/or external danger signals by specific sensors, followed by the nucleation and polymerization from sensor to downstream adaptor and then to the effector, caspase-1. Aberrant activation of inflammasomes promotes autoinflammatory diseases, cancer, neurodegeneration, and cardiometabolic disorders. Therefore, an equitable level of regulation is required to maintain the equilibrium between inflammasome activation and inhibition. Recent advancement in the structural and mechanistic understanding of inflammasome assembly potentiates the emergence of novel therapeutics against inflammasome-regulated diseases. In this review, we have comprehensively discussed the recent and updated insights into the structure of inflammasome components, their activation, interaction, mechanism of regulation, and finally, the formation of densely packed filamentous inflammasome complex that exists as micron-sized punctum in the cells and mediates the immune responses.

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NLRP3 inflammasome assembly is regulated by phosphorylation of the pyrin domain

Journal of Experimental Medicine ◽

10.1084/jem.20160933 ◽

2017 ◽

Vol 214 (6) ◽

pp. 1725-1736 ◽

Cited By ~ 113

Author(s):

Andrea Stutz ◽

Carl-Christian Kolbe ◽

Rainer Stahl ◽

Gabor L. Horvath ◽

Bernardo S. Franklin ◽

...

Keyword(s):

Pattern Recognition ◽

Cell Death ◽

Proinflammatory Cytokines ◽

Inflammasome Activation ◽

Phosphorylation Sites ◽

Danger Signals ◽

Pyrin Domain ◽

Charge Interaction ◽

Phosphatase 2A ◽

Recognition Receptor

NLRP3 is a cytosolic pattern recognition receptor that senses microbes and endogenous danger signals. Upon activation, NLRP3 forms an inflammasome with the adapter ASC, resulting in caspase-1 activation, release of proinflammatory cytokines and cell death. How NLRP3 activation is regulated by transcriptional and posttranslational mechanisms to prevent aberrant activation remains incompletely understood. Here, we identify three conserved phosphorylation sites in NLRP3 and demonstrate that NLRP3 activation is controlled by phosphorylation of its pyrin domain (PYD). Phosphomimetic residues in NLRP3 PYD abrogate inflammasome activation and structural modeling indicates that phosphorylation of the PYD regulates charge–charge interaction between two PYDs that are essential for NLRP3 activation. Phosphatase 2A (PP2A) inhibition or knock-down drastically reduces NLRP3 activation, showing that PP2A can license inflammasome assembly via dephosphorylating NLRP3 PYD. These results propose that the balance between kinases and phosphatases acting on the NLRP3 PYD is critical for NLRP3 activation.

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Inflammasomes inMycobacterium tuberculosis-Driven Immunity

Canadian Journal of Infectious Diseases and Medical Microbiology ◽

10.1155/2017/2309478 ◽

2017 ◽

Vol 2017 ◽

pp. 1-9 ◽

Cited By ~ 8

Author(s):

Sebastian Wawrocki ◽

Magdalena Druszczynska

Keyword(s):

Mycobacterium Tuberculosis ◽

Inflammatory Response ◽

Immune Responses ◽

Proinflammatory Cytokines ◽

Immune Cells ◽

Protein Complexes ◽

Inflammasome Activation ◽

Host Immune Responses ◽

Multimeric Protein

The development of effective innate and subsequent adaptive host immune responses is highly dependent on the production of proinflammatory cytokines that increase the activity of immune cells. The key role in this process is played by inflammasomes, multimeric protein complexes serving as a platform for caspase-1, an enzyme responsible for proteolytic cleavage of IL-1βand IL-18 precursors. Inflammasome activation, which triggers the multifaceted activity of these two proinflammatory cytokines, is a prerequisite for developing an efficient inflammatory response against pathogenicMycobacterium tuberculosis(M.tb). This review focuses on the role of NLRP3 and AIM2 inflammasomes inM.tb-driven immunity.

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Dynamics of in vivo ASC speck formation

The Journal of Cell Biology ◽

10.1083/jcb.201703103 ◽

2017 ◽

Vol 216 (9) ◽

pp. 2891-2909 ◽

Cited By ~ 19

Author(s):

Paola Kuri ◽

Nicole L. Schieber ◽

Thomas Thumberger ◽

Joachim Wittbrodt ◽

Yannick Schwab ◽

...

Keyword(s):

Electron Microscopy ◽

Cell Death ◽

Light And Electron Microscopy ◽

Three Dimensional ◽

Inflammasome Activation ◽

Caspase Activation ◽

Endogenous Gene ◽

Pyrin Domain ◽

Effector Caspase

Activated danger or pathogen sensors trigger assembly of the inflammasome adaptor ASC into specks, large signaling platforms considered hallmarks of inflammasome activation. Because a lack of in vivo tools has prevented the study of endogenous ASC dynamics, we generated a live ASC reporter through CRISPR/Cas9 tagging of the endogenous gene in zebrafish. We see strong ASC expression in the skin and other epithelia that act as barriers to insult. A toxic stimulus triggered speck formation and rapid pyroptosis in keratinocytes in vivo. Macrophages engulfed and digested that speck-containing, pyroptotic debris. A three-dimensional, ultrastructural reconstruction, based on correlative light and electron microscopy of the in vivo assembled specks revealed a compact network of highly intercrossed filaments, whereas pyrin domain (PYD) or caspase activation and recruitment domain alone formed filamentous aggregates. The effector caspase is recruited through PYD, whose overexpression induced pyroptosis but only after substantial delay. Therefore, formation of a single, compact speck and rapid cell-death induction in vivo requires a full-length ASC.

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Inhibitory pattern recognition receptors

Journal of Experimental Medicine ◽

10.1084/jem.20211463 ◽

2021 ◽

Vol 219 (1) ◽

Author(s):

Matevž Rumpret ◽

Helen J. von Richthofen ◽

Victor Peperzak ◽

Linde Meyaard

Keyword(s):

Pattern Recognition ◽

Cell Death ◽

Immune System ◽

Immune Responses ◽

Pattern Recognition Receptors ◽

Inhibitory Receptors ◽

Danger Signals ◽

Molecular Pattern ◽

Molecular Patterns ◽

Damage Associated Molecular Patterns

Pathogen- and damage-associated molecular patterns are sensed by the immune system’s pattern recognition receptors (PRRs) upon contact with a microbe or damaged tissue. In situations such as contact with commensals or during physiological cell death, the immune system should not respond to these patterns. Hence, immune responses need to be context dependent, but it is not clear how context for molecular pattern recognition is provided. We discuss inhibitory receptors as potential counterparts to activating pattern recognition receptors. We propose a group of inhibitory pattern recognition receptors (iPRRs) that recognize endogenous and microbial patterns associated with danger, homeostasis, or both. We propose that recognition of molecular patterns by iPRRs provides context, helps mediate tolerance to microbes, and helps balance responses to danger signals.

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Inflammasome Activation in Bovine Peripheral Blood-Derived Macrophages Is Associated with Actin Rearrangement

Animals ◽

10.3390/ani10040655 ◽

2020 ◽

Vol 10 (4) ◽

pp. 655

Author(s):

Amin Tahoun ◽

Kirsty Jensen ◽

Hanem El-Sharkawy ◽

David Gally ◽

Amira M. Rizk ◽

...

Keyword(s):

Cell Death ◽

Immune System ◽

Immune Responses ◽

Defense Mechanism ◽

Inflammasome Activation ◽

Host Immune System ◽

Bovine Macrophage ◽

The Relationship ◽

Actin Localization ◽

Actin Rearrangement

Inflammation is critical for infection control and acts as an arsenal defense mechanism against invading microbes through activation of the host immune system. It works via its inflammasome components to sense the dangerous invading microorganism and send messages to the immune system to destroy them. To date, the function of bovine macrophage inflammasome and its relationship with actin has not been identified. This study aimed to investigate the activation of bovine inflammasome by phase one flagellin from Salmonella typhimurium and its interaction with actin. Bovine monocyte-derived macrophages were prepared and challenged with S. typhimurium SL1344 phase one flagellin. The results demonstrated the relationship between the flagellin-based activation of inflammasome and actin rearrangement. The flagellin-based activation of inflammasome promoted the activation and co-localization of F-actin and the inflammasome complex. Actin was remodeled to different degrees according to the stage of inflammasome activation. The actin redistribution varied from polymerization to filopodia, while at the stage of pyroptotic cell death, actin was broken down and interacted with activated inflammasome complexes. In conclusion, flagellin-dependent inflammasome activation and actin localization to the inflammasome at the stage of pyroptotic cell death may be of importance for appropriate immune responses, pending further studies to explore the exact cross-linking between the inflammasome complex and actin.

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Dynamics of ASC speck formation during skin inflammatory responses in vivo

10.1101/111542 ◽

2017 ◽

Author(s):

Paola Kuri ◽

Nicole L. Schieber ◽

Thomas Thumberger ◽

Joachim Wittbrodt ◽

Yannick Schwab ◽

...

Keyword(s):

Cell Death ◽

Real Time ◽

Inflammatory Responses ◽

Full Length ◽

Inflammasome Activation ◽

Endogenous Gene ◽

Effector Caspase

AbstractActivated danger or pathogen sensors trigger assembly of the inflammasome adaptor ASC into specks, large signalling platforms considered hallmarks of inflammasome activation. Because a lack of in vivo tools has prevented the study of endogenous ASC dynamics, we generated a live ASC reporter through CRISPR/Cas9 tagging of the endogenous gene in zebrafish. We see strong ASC expression in the skin and other epithelia that act as barriers to insult. A toxic stimulus triggered speck formation and rapid pyroptosis in keratinocytes in vivo. Macrophages engulfed and digested this speck-containing pyroptotic debris. A 3D ultrastructural reconstruction based on CLEM of in vivo assembled specks revealed a compact network of highly intercrossed filaments, whereas PYD or CARD alone formed filamentous aggregates. The effector caspase is recruited through PYD, whose overexpression induced pyroptosis, but after substantial delay. Therefore, formation of a single compact speck and rapid cell death induction in vivo requires full-length ASC.One Sentence SummaryWith a new endogenous ASC real-time reporter we characterize speck dynamics in vivo as well as the concomitant pyroptosis speck formation causes in keratinocytes.

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ER stress, autophagy and immunogenic cell death in photodynamic therapy-induced anti-cancer immune responses

Photochemical & Photobiological Sciences ◽

10.1039/c3pp50333j ◽

2014 ◽

Vol 13 (3) ◽

pp. 474-487 ◽

Cited By ~ 102

Author(s):

Abhishek D. Garg ◽

Patrizia Agostinis

Keyword(s):

Cell Death ◽

Photodynamic Therapy ◽

Immune System ◽

Immune Responses ◽

Er Stress ◽

Cancer Cell ◽

Immunogenic Cell Death ◽

Danger Signals ◽

Anti Cancer

Few, selected anticancer therapeutic regimens like Hypericin-PDT are able to induce a promising kind of cancer cell demise called immunogenic cell death (ICD), which can activate the immune system owing to the spatiotemporally defined emission of danger signals.

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