scholarly journals EROS-mediated control of NOX2 and P2X7 biosynthesis

2021 ◽  
Author(s):  
Lyra O Randzavola ◽  
Paige M Mortimer ◽  
Emma C Garside ◽  
Elizabeth R Dufficy ◽  
Andrea Schejtman ◽  
...  
Keyword(s):  
Influenza Infection ◽  
Inflammasome Activation ◽  
Oxygen Species ◽  
Granulomatous Disease ◽  
Purine Receptors ◽  
Innate And Adaptive Immunity ◽  
Cell Responses ◽  
Phagocyte Nadph Oxidase ◽  
Severe Immunodeficiency

EROS (Essential for Reactive Oxygen Species) protein is indispensable for expression of the gp91phox-p22phox heterodimer of the phagocyte NADPH oxidase. EROS deficiency in humans causes the severe immunodeficiency, chronic granulomatous disease (CGD), but its mechanism of action remains unknown. We elucidate the role of EROS, showing it acts at the earliest stages of gp91phox maturation. It binds the immature 58kDa gp91phox directly, interacting with the OST glycosylation machinery and prevents gp91phox degradation. EROS also regulates the purine receptors P2X7 and P2X1 through direct interactions and P2X7 is almost absent in EROS deficiency. Accordingly, lack of EROS results in markedly abnormal P2X7 signalling, inflammasome activation and T cell responses. The loss of both ROS and P2X7 signalling leads to resistance to influenza infection. Our work identifies EROS as a highly selective chaperone for key proteins in innate and adaptive immunity and a rheostat for immunity to infection. It has profound implications for our understanding of immune physiology, immunodeficiency and gene therapy.

The role of IL-1 in gout: from bench to bedside

Rheumatology ◽  
2017 ◽  
Vol 57 (suppl_1) ◽  
pp. i12-i19 ◽  
Author(s):  
Alexander So ◽  
Alexandre Dumusc ◽  
Sonia Nasi
Keyword(s):  
Animal Studies ◽  
Reactive Oxygen Species Generation ◽  
Inflammasome Activation ◽  
Acute Gout ◽  
Oxygen Species ◽  
Biological Responses ◽  
Novel Approach ◽  
The Subject

Abstract The translation of our knowledge of the biology of MSU crystal-induced IL-1 secretion gives rise to new targets and therapeutic strategies in the treatment of acute gout. The NACHT, LRR and PYD domains-containing protein 3 inflammasome is key to this, and is the subject of intense research. Novel pathways that modulate inflammasome activation, reactive oxygen species generation and extracellular processing of IL-1 have been described and show promise in in vitro and animal studies. Meanwhile, blocking IL-1 by various IL-1 inhibitors has shown the validity of this concept. Patients with acute gout treated with these inhibitors showed positive clinical and biological responses. More work needs to be performed to assess the risk/benefit profile of anti-IL-1 therapies as well as to identify those who will benefit the most from this novel approach to the treatment of gout.

scholarly journals SARS-CoV-2 on the move: Reviewing Innate vs Acquired for Covid-19

2021 ◽  
Author(s):  
Sangam Banerjee
Keyword(s):  
Virulent Strain ◽  
Antigenic Drift ◽  
Innate And Adaptive Immunity ◽  
General Audience ◽  
Cell Responses ◽  
Complete Mapping ◽  
Prophylactic Measures ◽  
Antigenic Shift ◽  
Antibody Cocktail

In this article we have put down certain facts reported so far and raised some pertinent questions to understand the progress of Covid-19 disease. We have discussed the important role of innate immunity to tame Covid-19. Basics of innate and adaptive immunity has been discussed for general audience. Subsequently, we have discussed why immunity fails leading to ‘immunity escape’. We have asked and tried to address few concerns such as: Can vaccines drive the pathogen to mutate to a higher virulent strain?; Evolution of more virulent pathogens; Evidence of new variants; Evidence of variants evading immunity; Antibody cocktail demand for new design of vaccine; Evidence of SARS-CoV-2 evades T cell responses; Imperfect leaky vaccine; Complete Mapping of Mutations to the SARS-CoV-2 Spike Receptor-Binding Domain; Where is the originally identified SARS-CoV-2 (labeled as D614) found first in Wuhan, China; Deletion of spike glycoprotein itself: How to fix missing?; What is the present status?; To be or not to be vaccinated?; The challenge of antigenic drift and antigenic shift; What causes variant and can it be controlled?; A new dawn in the fight against the disease, to be or not to be worried?; Judging the risk “risk management”; Prophylactic measures for covid 19: Changing Diet and life style; Maneuvering the pandemic and finally the “Take away message”.

scholarly journals Hyperinflammation in chronic granulomatous disease and anti-inflammatory role of the phagocyte NADPH oxidase

2008 ◽  
Vol 30 (3) ◽  
pp. 255-271 ◽  
Author(s):  
Michela G. Schäppi ◽  
Vincent Jaquet ◽  
Dominique C. Belli ◽  
Karl-Heinz Krause
Keyword(s):  
Nadph Oxidase ◽  
Chronic Granulomatous Disease ◽  
Granulomatous Disease ◽  
Phagocyte Nadph Oxidase ◽  
Anti Inflammatory

scholarly journals Aldh2 Attenuates Stem Cell Factor/Kit-Dependent Signaling and Activation in Mast Cells

2019 ◽  
Vol 20 (24) ◽  
pp. 6216 ◽  
Author(s):  
Do-Kyun Kim ◽  
Young-Eun Cho ◽  
Byoung-Joon Song ◽  
Toshihiro Kawamoto ◽  
Dean D. Metcalfe ◽  
...  
Keyword(s):  
Mast Cell ◽  
Stem Cell ◽  
Mast Cells ◽  
Stem Cell Factor ◽  
Oxygen Species ◽  
Cell Reactivity ◽  
Downstream Signaling ◽  
Cell Responses ◽  
Kinase Phosphorylation

Mitochondrial aldehyde dehydrogenase (ALDH2) metabolizes endogenous and exogenous aldehydes and protects cells against oxidative injury. Inactivating genetic polymorphisms in humans are common and associate with alcohol flush reactions. However, whether mast cell Aldh2 activity impacts normal mast cell responses is unknown. Using bone marrow-derived mast cells from Aldh2 knockout mice, we found evidence for a role of mast cell Aldh2 in Kit-mediated responses. Aldh2-deficient mast cells showed enhanced Kit tyrosine kinase phosphorylation and activity after stimulation with its ligand (stem cell factor) and augmentation of downstream signaling pathways, including Stat4, MAPKs, and Akt. The activity of the phosphatase Shp-1, which attenuates Kit activity, was reduced in Aldh2−/− mast cells, along with an increase in reactive oxygen species, known to regulate Shp-1. Reduced Shp-1 activity concomitant with sustained Kit signaling resulted in greater proliferation following Kit engagement, and increased mediator and cytokine release when Aldh2−/− mast cells were co-stimulated via Kit and FcεRI. However, FcεRI-mediated signaling and responses were unaffected. Therefore, our findings reveal a functional role for mast cell intrinsic Aldh2 in the control of Kit activation and Kit-mediated responses, which may lead to a better understanding of mast cell reactivity in conditions related to ALDH2 polymorphisms.

Platelets as Modulators of Inflammation

2017 ◽  
Vol 44 (02) ◽  
pp. 091-101 ◽  
Author(s):  
Seok-Joo Kim ◽  
Rachelle Davis ◽  
Craig Jenne
Keyword(s):  
Endothelial Cell ◽  
Tissue Damage ◽  
Inflammatory Responses ◽  
Platelet Response ◽  
Platelet Activity ◽  
Disease Pathogenesis ◽  
Innate And Adaptive Immunity ◽  
Effector Cells ◽  
Cell Responses

AbstractPlatelets have classically been considered crucial effector cells in hemostasis, but now are increasingly recognized as players during inflammatory responses in innate and adaptive immunity. Platelets can recognize and kill invading pathogens, and, upon stimulation, also release a wide array of mediators that modify immune and endothelial cell responses. Increased platelet activity can protect the host against infectious insults; however, the excessive activity can lead to inflammation-mediated tissue damage. These critical roles highlight the necessity of balancing the platelet response at the intersection of hemostasis and inflammation. In this review, the authors present the current understanding of the inflammatory role of platelets. They also highlight recent findings on a modulator that links inflammation and deleterious tissue damage in disease pathogenesis.

scholarly journals Platelet-activating factor (PAF) mediates NLRP3-NEK7 inflammasome induction independently of PAFR

2019 ◽  
Vol 216 (12) ◽  
pp. 2838-2853 ◽  
Author(s):  
Meng Deng ◽  
Haitao Guo ◽  
Jason W. Tam ◽  
Brandon M. Johnson ◽  
W. June Brickey ◽  
...  
Keyword(s):  
Calcium Influx ◽  
Platelet Activating Factor ◽  
Inflammasome Activation ◽  
Oxygen Species ◽  
Mitochondrial Reactive Oxygen Species ◽  
Potassium Efflux ◽  
G Protein Coupled

The role of lipids in inflammasome activation remains underappreciated. The phospholipid, platelet-activating factor (PAF), exerts multiple physiological functions by binding to a G protein–coupled seven-transmembrane receptor (PAFR). PAF is associated with a number of inflammatory disorders, yet the molecular mechanism underlying its proinflammatory function remains to be fully elucidated. We show that multiple PAF isoforms and PAF-like lipids can activate the inflammasome, resulting in IL-1β and IL-18 maturation. This is dependent on NLRP3, ASC, caspase-1, and NEK7, but not on NLRC4, NLRP1, NLRP6, AIM2, caspase-11, or GSDMD. Inflammasome activation by PAF also requires potassium efflux and calcium influx but not lysosomal cathepsin or mitochondrial reactive oxygen species. PAF exacerbates peritonitis partly through inflammasome activation, but PAFR is dispensable for PAF-induced inflammasome activation in vivo or in vitro. These findings reveal that PAF represents a damage-associated signal that activates the canonical inflammasome independently of PAFR and provides an explanation for the ineffectiveness of PAFR antagonist in blocking PAF-mediated inflammation in the clinic.

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 Neutrophils drive alveolar macrophage IL-1β release during respiratory viral infection

Thorax ◽  
2017 ◽  
Vol 73 (6) ◽  
pp. 546-556 ◽  
Author(s):  
Teresa Peiró ◽  
Dhiren F Patel ◽  
Samia Akthar ◽  
Lisa G Gregory ◽  
Chloe J Pyle ◽  
...  
Keyword(s):  
Viral Infection ◽  
Alveolar Macrophage ◽  
Alveolar Macrophages ◽  
Nlrp3 Inflammasome ◽  
Influenza Infection ◽  
Receptor Protein ◽  
Inflammasome Activation ◽  
Respiratory Viral Infection ◽  
Inflammatory Phenotype

BackgroundAlveolar macrophages are sentinels of the airways that must exhibit immune restraint to innocuous antigens but elicit a robust inflammatory response to pathogenic threats. How distinction between these dichotomous functions is controlled is poorly defined.Neutrophils are the first responders to infection, and we hypothesised that they may free alveolar macrophages from their hyporesponsive state, promoting their activation. Activation of the inflammasome and interleukin (IL)-1β release is a key early inflammatory event that must be tightly regulated. Thus, the role of neutrophils in defining inflammasome activation in the alveolar macrophage was assessed.MethodsMice were infected with the X31 strain of influenza virus and the role of neutrophils in alveolar macrophage activation established through administration of a neutrophil-depleting (1A8) antibody.ResultsInfluenza elicited a robust IL-1β release that correlated (r=0.6849; p<0.001) with neutrophil infiltrate and was ablated by neutrophil depletion. Alveolar macrophages were shown to be the prominent source of IL-1β during influenza infection, and virus triggered the expression of Nod-like receptor protein 3 (NLRP3) inflammasome and pro-IL-1β in these cells. However, subsequent activation of the inflammasome complex and release of mature IL-1β from alveolar macrophages were critically dependent on the provision of a secondary signal, in the form of antimicrobial peptide mCRAMP, from infiltrating neutrophils.ConclusionsNeutrophils are critical for the activation of the NLRP3 inflammasome in alveolar macrophages during respiratory viral infection. Accordingly, we rationalise that neutrophils are recruited to the lung to confront a viable pathogenic threat and subsequently commit alveolar macrophages to a pro-inflammatory phenotype to combat infection.

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