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.

Eff ects of hyperbaric oxygen on NLRP3 infl ammasome activation in the brain aft er carbon monoxide poisoning

2020 ◽  
pp. 607-619
Author(s):  
Ya’nan Qi ◽  
◽  
Zhibao Guo ◽  
Huijun Hu ◽  
Xiang’en Meng ◽  
...  
Keyword(s):  
Carbon Monoxide ◽  
Nadph Oxidase ◽  
Hyperbaric Oxygen ◽  
Nlrp3 Inflammasome ◽  
Carbon Monoxide Poisoning ◽  
Enzyme Linked Immunosorbent Assay ◽  
Inflammasome Activation ◽  
Protein Levels ◽  
Nlrp3 Inflammasome Activation ◽  
Myelin Injury

Neuroinflammation plays an important role in brain damage after acute carbon monoxide poisoning (ACOP). The nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing (NLRP) 3 inflammasome triggers the activation of inflammatory caspases and maturation of interleukin (IL)-1β and -18, and has been linked to various human autoinflammatory and autoimmune diseases. In this study we investigated the effects of hyperbaric oxygen (HBO2) on NLRP3 inflammasome activation after ACOP. Mice were randomly divided into four groups: sham group (exposure to normobaric air – i.e., 21% O2 at 1 atmosphere absolute); HBO2-only group; CO + normobaric air group; and CO + HBO2 group. Cognitive function was evaluated with the Morris water maze; myelin injury was assessed by Fluoro-Myelin GreenTM fluorescent myelin staining and myelin basic protein (MBP) immunostaining; and mRNA and protein levels of NLRP3 inflammasome complex proteins were measured by quantitative real-time PCR and Western blot, respectively. Additionally, serum and brain levels of IL-1β and -18 and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase were determined by enzyme-linked immunosorbent assay. It was found that HBO2 improved learning and memory, and alleviated myelin injury in mice subjected to acute CO exposure. Furthermore, HBO2 decreased NLRP3, absent in melanoma 2 (AIM2), caspase-1, and apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain mRNA and protein levels, and reduced brain and serum concentrations of IL-1β and -18 and NADPH oxidase. These results indicate that HBO2 suppresses the inflammatory response after ACOP by blocking NLRP3 inflammasome activation, thereby alleviating cognitive deficits.

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 NADPH Oxidase 2 Regulates NLRP3 Inflammasome Activation in the Brain after Traumatic Brain Injury

2017 ◽  
Vol 2017 ◽  
pp. 1-18 ◽  
Author(s):  
Merry W. Ma ◽  
Jing Wang ◽  
Krishnan M. Dhandapani ◽  
Darrell W. Brann
Keyword(s):  
Oxidative Stress ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Nadph Oxidase ◽  
Nlrp3 Inflammasome ◽  
Healing Process ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Nadph Oxidase 2

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. After the initial primary mechanical injury, a complex secondary injury cascade involving oxidative stress and neuroinflammation follows, which may exacerbate the injury and complicate the healing process. NADPH oxidase 2 (NOX2) is a major contributor to oxidative stress in TBI pathology, and inhibition of NOX2 is neuroprotective. The NLRP3 inflammasome can become activated in response to oxidative stress, but little is known about the role of NOX2 in regulating NLRP3 inflammasome activation following TBI. In this study, we utilized NOX2 knockout mice to study the role of NOX2 in mediating NLRP3 inflammasome expression and activation following a controlled cortical impact. Expression of NLRP3 inflammasome components NLRP3 and apoptosis-associated speck-like protein containing a CARD (ASC), as well as its downstream products cleaved caspase-1 and interleukin-1β (IL-1β), was robustly increased in the injured cerebral cortex following TBI. Deletion of NOX2 attenuated the expression, assembly, and activity of the NLRP3 inflammasome via a mechanism that was associated with TXNIP, a sensor of oxidative stress. The results support the notion that NOX2-dependent inflammasome activation contributes to TBI pathology.

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