Role of NRROS in microglia and perivascular macrophages in the brain
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE96939 | GEO | 2017/04/07
SECONDARY ACCESSION(S): PRJNA380301
REPOSITORIES: GEO
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Project description:Aim of this experiment was to characterize whether SPP1 released from the hippocampal perivascular space could imprint microglia transcriptional states. We performed scRNA-seq analysis on sorted CD140a+ perivascular fibroblast (PVF), CD45highCD11intCD206+ perivascular macrophage (PVM) and CD45intCD11intCX3CR1high microglial cell from dissected hippocampi of 6-month old wild type vs SPP1KO/KO vs AppNL-F mice vs AppNL-FxSpp1KO/KO mice. Cells were isolated from dissected hippocampi as previously described (Sala Frigerio et al.,2019).
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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.
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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.
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Project description:Previous studies have proposed that production of reactive oxygen species (ROS) is an important contributor to renal injury and inflammation following exposure to oxalate or calcium-oxalate crystals. The present study was conducted to determine, utilizing global transcriptome analyses, if the NADPH oxidase system is activated in kidneys of rats fed a diet leading to hyperoxaluria and crystal deposition. HLP was used to induce hyperoxaluria. Hyperoxaluria will lead to crystallization and up regulation of various NADPH oxidase subunits followed by increased expression of different specific genes. It is our hypothesis that crystallization induces inflammation of the kidneys via the activation of renin-angiotensin system (RAS) and production of reactive oxygen species (ROS) through NADPH oxidase complex. Apocynin was used to block hyperoxaluria and production of reactive oxygen species (ROS) with the inhibition of NADPH oxidase system as Apocynin inhibits membrane translocation of p47 subunit of NADPH oxidase.
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Project description:The regulation of protein function by reversible oxidation is increasingly recognized as a key mechanism for the control of cellular signalling, modulating crucial biological processes such cell differentiation. In this scenario, the NADPH oxidases must occupy a prominent position. Our results show that haematopoietic stem and progenitor cells (HSPCs) express three p22phox-dependent NADPH oxidases members (Nox1, Nox2 and Nox4). By deleting the p22phox coding gene (Cyba), here we have analysed the importance of this family of enzymes during in vivo haematopoiesis. Cyba-/- mice show a myeloid bias in detriment of B-cells differentiation, and an enrichment of HSPCs populations. By means of haematopoietic transplant experiments we have also tried to dissect the specific role of the NADPH oxidases. While the absence of Nox1 or Nox2 provides an advantage of reconstitution, the lack of Nox4 rendered the opposite result, what suggests a functional specificity among the different NADPH oxidases. Regarding signalling pathways, the activation of AKT and STAT5 is hampered in Cyba-/- cells, the later due to the downregulation of STAT5 protein. This is in line with the diminished response to IL-7 shown by our results, what could explain defective B-cells development observed in Cyba-/- mice, supporting the requirement of NADPH oxidase activity for terminal B-cell differentiation.
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2023-05-03 | PXD032104 | Pride
Project description:Previous studies have proposed that production of reactive oxygen species (ROS) is an important contributor to renal injury and inflammation following exposure to oxalate or calcium-oxalate crystals. The present study was conducted to determine, utilizing global transcriptome analyses, if the NADPH oxidase system is activated in kidneys of rats fed a diet leading to hyperoxaluria and crystal deposition. HLP was used to induce hyperoxaluria. Hyperoxaluria will lead to crystallization and up regulation of various NADPH oxidase subunits followed by increased expression of different specific genes. It is our hypothesis that crystallization induces inflammation of the kidneys via the activation of renin-angiotensin system (RAS) and production of reactive oxygen species (ROS) through NADPH oxidase complex. Apocynin was used to block hyperoxaluria and production of reactive oxygen species (ROS) with the inhibition of NADPH oxidase system as Apocynin inhibits membrane translocation of p47 subunit of NADPH oxidase. The present study was designed based on NADPH oxidase system and rats were divided into 4 groups (n= 6/group). Group 1 was fed regular rat chow diet, Group 2 received regular rat chow diet supplemented with 5% (Hydroxy-L-Proline) HLP, Group 3 received rat chow diet with 4 mmol Apocynin to drink, and Group 4 received regular rat chow diet with 5% HLP and 4 mmol Apocynin. After 28 days each rat was euthanized, their kidneys freshly explanted and dissected to obtain both cortex and medulla tissues. So the 4 groups were divided into cortex and medulla forming 8 groups. RNA was isolated from all the 8 specimens
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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.
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