The role of phagocyte NADPH Oxidase (NOX2) in modulating the antimicrobial and inflammatory functions of mouse neutrophils
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PROVIDER: PRJNA1079342 | ENA |
REPOSITORIES: ENA
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Project description:Urinary tract infections (UTI) stand as one of the most prevalent infections worldwide. Uropathogenic Escherichia coli (UPEC) is the primary cause of UTI, instigating 75% of uncomplicated and 65% of complicated UTIs. Innate immune cells play pivotal roles in eliminating invading uropathogens and represent a potential therapeutic target for UTI prevention and treatment. Previous studies in our laboratory demonstrated that selective depletion of neutrophils during experimental UTI, results in an uncontrolled infection and augmented bladder and kidney pathologies. However, the exact antimicrobial mechanisms employed by neutrophils to eliminate multi-drug resistant uropathogens, such as UPEC, and resolve UTI remain poorly understood. Our dataset provides insight of the multifaceted role of neutrophil NOX2 in UPEC elimination and regulation of inflammatory and effector functions of these innate immune cells. Our transcriptome analyses revealed a heightened pro-inflammatory profile in NOX2-deficient neutrophils compared to WT neutrophils after UPEC stimulation.
2025-02-28 | GSE256399 | GEO
Project description:The phagocyte NADPH oxidase is critical for host defence, and EROS (Essential for Reactive Oxygen Species) protein is indispensable for expression of its gp91phox-p22phox heterodimer. EROS deficiency in humans is a recently described cause of chronic granulomatous disease (CGD), but its mechanism of action remains unknown. We show EROS binds the immature 58kDa gp91phox directly prior to glycosylation and heme incorporation, thus preventing its degradation. EROS interacts with the oligosaccharyl transferase complex (OST) present at the endoplasmic reticulum. Inhibition of the OST complex suppresses EROS-mediated stabilisation of the 58kDa, providing insight into the early steps of gp91phox biosynthesis. EROS also regulates the purine receptors P2X7 and P2X1 through direct interactions. Accordingly, lack of EROS results in markedly abnormal P2X7 signalling, inflammasome activation and T cell responses. The loss of both the phagocyte respiratory burst and P2X7 signalling lead to resistance to influenza infection. Our work identifies EROS as the first described highly selective chaperone controlling key proteins in innate and adaptive immunity. It has profound implications for immune physiology, immunodeficiency and gene therapy.
2022-11-30 | PXD025149 | Pride
Project description:Mycobacterium tuberculosis’success as a pathogen comes from itsability to evade degradation by macrophages. Normally macro-phages clear microorganisms that activate pathogen-recognitionreceptors (PRRs) through a lysosomal-trafficking pathway called“LC3-associated phagocytosis”(LAP). AlthoughM.tuberculosisac-tivates numerous PRRs, for reasons that are poorly understoodLAP does not substantially contribute toM.tuberculosiscontrol.LAP depends upon reactive oxygen species (ROS) generated byNADPH oxidase, butM.tuberculosisfails to generate a robustoxidative response. Here, we show that CpsA, a LytR-CpsA-Psr(LCP) domain-containing protein, is required forM.tuberculosisto evade killing by NADPH oxidase and LAP. Unlike phagosomescontaining wild-type bacilli, phagosomes containing theΔcpsAmutant recruited NADPH oxidase, produced ROS, associated withLC3, and matured into antibacterial lysosomes. Moreover, CpsAwas sufficient to impair NADPH oxidase recruitment to fungal par-ticles that are normally cleared by LAP. Intracellular survival of theΔcpsAmutant was largely restored in macrophages missing LAPcomponents (Nox2,Rubicon,Beclin,Atg5,Atg7,orAtg16L1) butnot in macrophages defective in a related, canonical autophagypathway (Atg14,Ulk1,orcGAS). TheΔcpsAmutant was highlyimpaired in vivo, and its growth was partially restored in micedeficient in NADPH oxidase,Atg5,orAtg7, demonstrating thatCpsA makes a significant contribution to the resistance ofM.tu-berculosisto NADPH oxidase and LC3 trafficking in vivo. Overall,our findings reveal an essential role of CpsA in innate immuneevasion and suggest that LCP proteins have functions beyond theirpreviously known role in cell-wall metabolism.
2019-12-13 | GSE141931 | GEO
Project description:The leukocyte NADPH oxidase 2 (NOX2) plays a key role in pathogen killing and immunoregulation
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Project description:Anaerobic respiration of host-derived methionine sulfoxide protects intracellular Salmonella from the phagocyte NADPH oxidase
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Project description:Obesity is linked to an increased risk of atrial fibrillation (AF) via increased oxidative stress. While NADPH oxidase II (NOX2), a major source of oxidative stress and reactive oxygen species (ROS) in the heart predisposes to AF, the underlying mechanisms remain unclear. Here, we studied NOX2-mediated ROS production in obesity-mediated AF using Nox2-knock-out (KO) mice and mature human induced pluripotent stem cell-derived atrial cardiomyocytes (hiPSC-aCMs). Diet-induced obesity (DIO) mice and hiPSC-aCMs treated with palmitic acid (PA) were infused with a NOX blocker (apocynin) and a NOX2-specific inhibitor, respectively. We showed that NOX2 inhibition normalized atrial action potential duration and abrogated obesity-mediated ion channel remodeling with reduced AF burden. Unbiased transcriptomics analysis revealed that NOX2 mediates atrial remodeling in obesity-mediated AF in DIO mice, PA-treated hiPSC-aCMs, and human atrial tissue from obese individuals by upregulation of paired-like homeodomain transcription factor 2 (PITX2). Furthermore, hiPSC-aCMs treated with hydrogen peroxide, a NOX2 surrogate, displayed increased PITX2 expression, establishing a mechanistic link between increased NOX2-mediated ROS production and modulation of PITX2. Our findings offer insights into possible mechanisms through which obesity triggers AF and support NOX2 inhibition as a potential novel prophylactic or adjunctive therapy for patients with obesity-mediated AF.
2024-10-09 | GSE271748 | GEO
Project description:NADPH dependent phagocytic oxidase, by producing hydroxyradicals such as hydrogen peroxide, is essential for host defense against Salmonella infection. We used gene array analysis to identify Salmonella enterica serovar Typhimurium genes regulated by NADPH dependent phagocytic oxidase intracellularly in comparison to those expressed in vitro by hydrogen peroxide.
2007-05-02 | E-MEXP-1089 | biostudies-arrayexpress
Project description:Small nucleolar RNAs (snoRNAs) guide nucleotide modifications of cellular RNAs in the nucleus. We have previously shown that box C/D snoRNAs from the Rpl13a locus are unexpected mediators of physiologic oxidative stress, independent of their predicted ribosomal RNA modifications. Here, we demonstrate that oxidative stress induced by doxorubicin causes rapid cytoplasmic accumulation of the Rpl13a snoRNAs through a mechanism that requires superoxide and a nuclear splice variant of NADPH oxidase. RNA-sequencing analysis reveals that box C/D snoRNAs as a class are present in the cytoplasm, where their levels are dynamically regulated by NADPH oxidase. These findings suggest that snoRNAs may orchestrate the response to environmental stress through molecular interactions outside of the nucleus.
2015-03-20 | GSE67050 | GEO
Project description:The leukocyte NADPH oxidase 2 (NOX2) plays a key role in pathogen killing and immunoregulation. Genetic defects in NOX2 result in chronic granulomatous disease (CGD), associated with microbial infections and inflammatory disorders, often involving the lung. Alveolar macrophages (AM) are the predominant immune cell in the airways at steady state, and limiting their activation is important given constant exposure to inhaled materials, yet the importance of NOX2 in this process is not well-understood. Here, we show a previously undescribed role for NOX2 in maintaining lung homeostasis by suppressing AM activation, as studied using CGD mice or mice with selective loss of NOX2 primarily in macrophages. AM lacking NOX2 have increased cytokine responses to TLR2 and TLR4 stimulation ex vivo. Moreover, between 4 and 12 weeks of age, mice with global NOX2 deletion developed an activated CD11bhigh subset of AM with epigenetic and transcriptional profiles reflecting immune activation compared to WT AM. The presence of CD11bhigh AM in CGD mice correlated with increased numbers of alveolar neutrophils and proinflammatory cytokines at steady state as well as increased lung inflammation following insults. Moreover, deletion of NOX2 primarily in macrophages was sufficient for mice to develop an activated CD11bhigh AM subset and accompanying pro-inflammatory sequela. Additionally, we showed that the altered resident macrophage transcriptional profile in the absence of NOX2 is tissue-specific as these changes were not seen in resident peritoneal macrophages. Thus, these data demonstrate that absence of NOX2 in alveolar macrophages leads to their pro-inflammatory remodeling and dysregulates alveolar homeostasis.
2022-04-03 | GSE198769 | GEO
Project description:Increased intracellular generation of reactive oxygen species [ROS] has been implicated in the pathology of metabolic [diabetes] and neurodegenerative [Alzheimer's] diseases. Accumulating evidence suggests NADPH oxidases [Noxs] as the principal source for cellular ROS in humans. Of this class of enzymes, the phagocyte-like Nox [Nox2] has come under intense scrutiny as one of the "culprits" for the induction of cellular damage culminating in the onset of diabetes and its complications. Functional regulation of Nox2 is fairly complex due to its membranous [gp91(phox), p22(phox)] and cytosolic [p40(phox), p47(phox), p67(phox) and Rac1] cores, which require specific post-translational modification steps [phosphorylation and lipidation] for their membrane association. Therefore, optimal efficacy of Nox2 depends upon precise regulation of these signaling steps followed by translocation of the cytosolic components to the membrane. Interestingly, numerous recent studies have reported sustained activation of Nox2, ROS-derived oxidative stress, and cellular dysfunction in in vitro and in vivo models of glucolipotoxicity and diabetes. These investigations employed a variety of cell-permeable peptides and pharmacological inhibitors to impede Nox2 holoenzyme assembly and activation in pancreatic islet β-cells, cardiomyocytes and retinal endothelial cells under conditions of glucolipotoxicity and diabetes. Herein, we highlight the existing evidence to implicate Nox2 as the "trigger" of cellular damage, and identify critical gaps in our current understanding that need to be addressed to further affirm the roles of Nox2 as a potential therapeutic target for the treatment of diabetes and other metabolic disorders.
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