Pathogen‐associated molecular patterns and extracellular Hsp70 interplay in NLRP3 inflammasome activation in monocytic and bronchial epithelial cellular models of COPD exacerbations

Apmis ◽  
2020 ◽  
Author(s):  
Lada Rumora ◽  
Iva Hlapčić ◽  
Andrea Hulina‐Tomašković ◽  
Anita Somborac‐Bačura ◽  
Martina Bosnar ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Bronchial Epithelial ◽  
Copd Exacerbations ◽  
Cellular Models ◽  
Nlrp3 Inflammasome Activation ◽  
Molecular Patterns

scholarly journals The Roles of Endoplasmic Reticulum in NLRP3 Inflammasome Activation

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1219 ◽  
Author(s):  
Yang Zhou ◽  
Zhizi Tong ◽  
Songhong Jiang ◽  
Wenyan Zheng ◽  
Jianjun Zhao ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Nlrp3 Inflammasome ◽  
Critical Role ◽  
Immune Defense ◽  
Inflammasome Activation ◽  
Nucleotide Binding Domain ◽  
Cholesterol Trafficking ◽  
Pyrin Domain ◽  
Nlrp3 Inflammasome Activation ◽  
Molecular Patterns

The NLRP3 (nucleotide-binding domain, leucine-rich-repeat-containing family, pyrin domain-containing 3) inflammasome senses pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), and activates caspase-1, which provokes release of proinflammatory cytokines such as interleukin-1β (IL-1β) and IL-18 as well as pyroptosis to engage in innate immune defense. The endoplasmic reticulum (ER) is a large and dynamic endomembrane compartment, critical to cellular function of organelle networks. Recent studies have unveiled the pivotal roles of the ER in NLRP3 inflammasome activation. ER–mitochondria contact sites provide a location for NLRP3 activation, its association with ligands released from or residing in mitochondria, and rapid Ca2+ mobilization from ER stores to mitochondria. ER-stress signaling plays a critical role in NLRP3 inflammasome activation. Lipid perturbation and cholesterol trafficking to the ER activate the NLRP3 inflammasome. These findings emphasize the importance of the ER in initiation and regulation of the NLRP3 inflammasome.

scholarly journals Distinct Molecular Mechanisms Underlying Potassium Efflux for NLRP3 Inflammasome Activation

2020 ◽  
Vol 11 ◽  
Author(s):  
Ziwei Xu ◽  
Zi-mo Chen ◽  
Xiaoyan Wu ◽  
Linjie Zhang ◽  
Ying Cao ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Inflammasome Activation ◽  
Potassium Efflux ◽  
Pannexin 1 ◽  
Nlrp3 Inflammasome Activation ◽  
K2p Channels ◽  
Pore Forming Proteins ◽  
Molecular Patterns

The NLRP3 inflammasome is a core component of innate immunity, and dysregulation of NLRP3 inflammasome involves developing autoimmune, metabolic, and neurodegenerative diseases. Potassium efflux has been reported to be essential for NLRP3 inflammasome activation by structurally diverse pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). Thus, the molecular mechanisms underlying potassium efflux to activate NLRP3 inflammasome are under extensive investigation. Here, we review current knowledge about the distinction channels or pore-forming proteins underlying potassium efflux for NLRP3 inflammasome activation with canonical/non-canonical signaling or following caspase-8 induced pyroptosis. Ion channels and pore-forming proteins, including P2X7 receptor, Gasdermin D, pannexin-1, and K2P channels involved present viable therapeutic targets for NLRP3 inflammasome related diseases.

scholarly journals Regulation of the NLRP3 Inflammasome by Post-Translational Modifications and Small Molecules

2021 ◽  
Vol 11 ◽  
Author(s):  
Jin Kyung Seok ◽  
Han Chang Kang ◽  
Yong-Yeon Cho ◽  
Hye Suk Lee ◽  
Joo Young Lee
Keyword(s):  
Small Molecules ◽  
Nlrp3 Inflammasome ◽  
Intracellular Signaling ◽  
Defense Mechanism ◽  
Therapeutic Strategies ◽  
The Body ◽  
Inflammasome Activation ◽  
Post Translational Modifications ◽  
Nlrp3 Inflammasome Activation ◽  
Molecular Patterns

Inflammation is a host protection mechanism that eliminates invasive pathogens from the body. However, chronic inflammation, which occurs repeatedly and continuously over a long period, can directly damage tissues and cause various inflammatory and autoimmune diseases. Pattern recognition receptors (PRRs) respond to exogenous infectious agents called pathogen-associated molecular patterns and endogenous danger signals called danger-associated molecular patterns. Among PRRs, recent advancements in studies of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome have established its significant contribution to the pathology of various inflammatory diseases, including metabolic disorders, immune diseases, cardiovascular diseases, and cancer. The regulation of NLRP3 activation is now considered to be important for the development of potential therapeutic strategies. To this end, there is a need to elucidate the regulatory mechanism of NLRP3 inflammasome activation by multiple signaling pathways, post-translational modifications, and cellular organelles. In this review, we discuss the intracellular signaling events, post-translational modifications, small molecules, and phytochemicals participating in the regulation of NLRP3 inflammasome activation. Understanding how intracellular events and small molecule inhibitors regulate NLRP3 inflammasome activation will provide crucial information for elucidating the associated host defense mechanism and the development of efficient therapeutic strategies for chronic diseases.

scholarly journals Ethyl Pyruvate Attenuates Microglial NLRP3 Inflammasome Activation via Inhibition of HMGB1/NF-κB/miR-223 Signaling

Antioxidants ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 745
Author(s):  
Melis Olcum ◽  
Kemal Ugur Tufekci ◽  
Devrim Yagmur Durur ◽  
Bora Tastan ◽  
Irem Nur Gokbayrak ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Ethyl Pyruvate ◽  
Metabolic Effects ◽  
Inflammasome Activation ◽  
Neuroprotective Effects ◽  
Cellular Models ◽  
Nlrp3 Inflammasome Activation ◽  
Parkinson’S Diseases ◽  
Anti Inflammatory ◽  
The Impact

Ethyl pyruvate is a molecule with anti-inflammatory and pro-metabolic effects. Ethyl pyruvate has been shown to ameliorate the clinical and pathological findings of neurodegenerative diseases such as Alzheimer’s and Parkinson’s Diseases in rodents. Its anti-inflammatory and neuroprotective effects are widely investigated in animal and cellular models. Our study aimed to investigate the mechanism of the impact of Ethyl pyruvate on NLRP3 inflammasome activation in the N9 microglial cell line. Our results indicated that ethyl pyruvate significantly suppressed LPS and ATP-induced NLRP3 inflammasome activation, decreased active caspase-1 level, secretion of IL-1β and IL-18 cytokines, and reduced the level of pyroptotic cell death resulting from inflammasome activation. Furthermore, ethyl pyruvate reduced the formation of total and mitochondrial ROS and suppressed inflammasome-induced HMGB1 upregulation and nuclear NF-κB translocation and reversed the inflammasome activation-induced miRNA expression profile for miR-223 in N9 cells. Our study suggests that ethyl pyruvate effectively suppresses the NLRP3 inflammasome activation in microglial cells regulation by miR-223 and NF-κB/HMGB1 axis.

Human NLRP3 inflammasome activation is Nox1-4 independent

Blood ◽  
2010 ◽  
Vol 115 (26) ◽  
pp. 5398-5400 ◽  
Author(s):  
Robin van Bruggen ◽  
M. Yavuz Köker ◽  
Machiel Jansen ◽  
Michel van Houdt ◽  
Dirk Roos ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Nlrp3 Inflammasome ◽  
Interleukin 1 ◽  
Inflammasome Activation ◽  
Oxygen Species ◽  
Granulomatous Disease ◽  
Primary Cells ◽  
Proteolytic Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Molecular Patterns

Abstract The NLRP3 inflammasome can be activated by pathogen-associated molecular patterns or endogenous danger-associated molecular patterns. The activation of the NLRP3 inflammasome results in proteolytic activation and secretion of cytokines of the interleukin-1 (IL-1) family. The precise mode of activation of the NLRP3 inflammasome is still elusive, but has been postulated to be mediated by reactive oxygen species (ROS) generated by an NADPH oxidase. Using primary cells from chronic granulomatous disease (CGD) patients lacking expression of p22phox, a protein that is required for the function of Nox1-4, we show that cells lacking NADPH oxidase activity are capable of secreting normal amounts of IL-1β. Thus, we provide evidence that activation of the NLRP3 inflammasome does not depend on ROS generated from an NADPH oxidase.

scholarly journals Cellular Models and Assays to Study NLRP3 Inflammasome Biology

2020 ◽  
Vol 21 (12) ◽  
pp. 4294 ◽  
Author(s):  
Giovanni Zito ◽  
Marco Buscetta ◽  
Maura Cimino ◽  
Paola Dino ◽  
Fabio Bucchieri ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammatory Diseases ◽  
Special Focus ◽  
Inflammasome Activation ◽  
Cellular Models ◽  
Downstream Effects ◽  
Wide Range ◽  
Molecular Patterns ◽  
Pro Inflammatory Cytokines

The NLRP3 inflammasome is a multi-protein complex that initiates innate immunity responses when exposed to a wide range of stimuli, including pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs). Inflammasome activation leads to the release of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18 and to pyroptotic cell death. Over-activation of NLRP3 inflammasome has been associated with several chronic inflammatory diseases. A deep knowledge of NLRP3 inflammasome biology is required to better exploit its potential as therapeutic target and for the development of new selective drugs. To this purpose, in the past few years, several tools have been developed for the biological characterization of the multimeric inflammasome complex, the identification of the upstream signaling cascade leading to inflammasome activation, and the downstream effects triggered by NLRP3 activation. In this review, we will report cellular models and cellular, biochemical, and biophysical assays that are currently available for studying inflammasome biology. A special focus will be on those models/assays that have been used to identify NLRP3 inhibitors and their mechanism of action.

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