Phagocyte NADPH oxidase and specific immunity

2015 ◽  
Vol 128 (10) ◽  
pp. 635-648 ◽  
Author(s):  
Julien Cachat ◽  
Christine Deffert ◽  
Stephanie Hugues ◽  
Karl-Heinz Krause
Keyword(s):  
Dendritic Cells ◽  
Nadph Oxidase ◽  
Cell Fate ◽  
B Lymphocytes ◽  
Antigen Processing ◽  
Ros Generation ◽  
Cell Fate Decisions ◽  
Specific Immunity ◽  
Phagocyte Nadph Oxidase ◽  
The Impact

The phagocyte NADPH oxidase NOX2 produces reactive oxygen species (ROS) and is a well-known player in host defence. However, there is also increasing evidence for a regulatory role of NOX2 in adaptive immunity. Deficiency in phagocyte NADPH oxidase causes chronic granulomatous disease (CGD) in humans, a condition that can also be studied in CGD mice. Clinical observations in CGD patients suggest a higher susceptibility to autoimmune diseases, in particular lupus, idiopathic thrombocytopenic purpura and rheumatoid arthritis. In mice, a strong correlation exists between a polymorphism in a NOX2 subunit and the development of autoimmune arthritis. NOX2 deficiency in mice also favours lupus development. Both CGD patients and CGD mice exhibit increased levels of immunoglobulins, including autoantibodies. Despite these phenotypes suggesting a role for NOX2 in specific immunity, mechanistic explanations for the typical increase of CGD in autoimmune disease and antibody levels are still preliminary. NOX2-dependent ROS generation is well documented for dendritic cells and B-lymphocytes. It is unclear whether T-lymphocytes produce ROS themselves or whether they are exposed to ROS derived from dendritic cells during the process of antigen presentation. ROS are signalling molecules in virtually any cell type, including T- and B-lymphocytes. However, knowledge about the impact of ROS-dependent signalling on T- and B-lymphocyte phenotype and response is still limited. ROS might contribute to Th1/Th2/Th17 cell fate decisions during T-lymphocyte activation and might enhance immunoglobulin production by B-lymphocytes. In dendritic cells, NOX2-derived ROS might be important for antigen processing and cell activation.

scholarly journals Subplasmalemmal hydrogen peroxide triggers calcium influx in gonadotropes

2018 ◽  
Vol 293 (41) ◽  
pp. 16028-16042 ◽  
Author(s):  
An K. Dang ◽  
Nathan L. Chaplin ◽  
Dilyara A. Murtazina ◽  
Ulrich Boehm ◽  
Colin M. Clay ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Calcium Channels ◽  
Nadph Oxidase ◽  
Calcium Channel ◽  
Anterior Pituitary ◽  
Calcium Influx ◽  
Ros Generation ◽  
Primary Mouse ◽  
The Impact ◽  
Stimulation Of

Gonadotropin-releasing hormone (GnRH) stimulation of its eponymous receptor on the surface of endocrine anterior pituitary gonadotrope cells (gonadotropes) initiates multiple signaling cascades that culminate in the secretion of luteinizing and follicle-stimulating hormones, which have critical roles in fertility and reproduction. Enhanced luteinizing hormone biosynthesis, a necessary event for ovulation, requires a signaling pathway characterized by calcium influx through L-type calcium channels and subsequent activation of the mitogen-activated protein kinase extracellular signal-regulated kinase (ERK). We previously reported that highly localized subplasmalemmal calcium microdomains produced by L-type calcium channels (calcium sparklets) play an essential part in GnRH-dependent ERK activation. Similar to calcium, reactive oxygen species (ROS) are ubiquitous intracellular signaling molecules whose subcellular localization determines their specificity. To investigate the potential influence of oxidant signaling in gonadotropes, here we examined the impact of ROS generation on L-type calcium channel function. Total internal reflection fluorescence (TIRF) microscopy revealed that GnRH induces spatially restricted sites of ROS generation in gonadotrope-derived αT3-1 cells. Furthermore, GnRH-dependent stimulation of L-type calcium channels required intracellular hydrogen peroxide signaling in these cells and in primary mouse gonadotropes. NADPH oxidase and mitochondrial ROS generation were each necessary for GnRH-mediated stimulation of L-type calcium channels. Congruently, GnRH increased oxidation within subplasmalemmal mitochondria, and L-type calcium channel activity correlated strongly with the presence of adjacent mitochondria. Collectively, our results provide compelling evidence that NADPH oxidase activity and mitochondria-derived hydrogen peroxide signaling play a fundamental role in GnRH-dependent stimulation of L-type calcium channels in anterior pituitary gonadotropes.

scholarly journals Theoretical study of the impact of adaptation on cell-fate heterogeneity and fractional killing

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Julien Hurbain ◽  
Darka Labavić ◽  
Quentin Thommen ◽  
Benjamin Pfeuty
Keyword(s):  
Cell Fate ◽  
Stochastic Dynamics ◽  
Biochemical Networks ◽  
Stochastic Bifurcation ◽  
Modeling Framework ◽  
Life And Death ◽  
Cell Fate Decisions ◽  
Wide Range ◽  
Adaptation Response ◽  
The Impact

Abstract Fractional killing illustrates the cell propensity to display a heterogeneous fate response over a wide range of stimuli. The interplay between the nonlinear and stochastic dynamics of biochemical networks plays a fundamental role in shaping this probabilistic response and in reconciling requirements for heterogeneity and controllability of cell-fate decisions. The stress-induced fate choice between life and death depends on an early adaptation response which may contribute to fractional killing by amplifying small differences between cells. To test this hypothesis, we consider a stochastic modeling framework suited for comprehensive sensitivity analysis of dose response curve through the computation of a fractionality index. Combining bifurcation analysis and Langevin simulation, we show that adaptation dynamics enhances noise-induced cell-fate heterogeneity by shifting from a saddle-node to a saddle-collision transition scenario. The generality of this result is further assessed by a computational analysis of a detailed regulatory network model of apoptosis initiation and by a theoretical analysis of stochastic bifurcation mechanisms. Overall, the present study identifies a cooperative interplay between stochastic, adaptation and decision intracellular processes that could promote cell-fate heterogeneity in many contexts.

scholarly journals Quantifying the Stability of Coupled Genetic and Epigenetic Switches With Variational Methods

2021 ◽  
Vol 11 ◽  
Author(s):  
Amogh Sood ◽  
Bin Zhang
Keyword(s):  
Gene Regulation ◽  
Transcription Factors ◽  
Cell Fate ◽  
Histone Modifications ◽  
Regulatory Networks ◽  
Variational Principles ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Cell Fate Decisions ◽  
The Impact

The Waddington landscape provides an intuitive metaphor to view development as a ball rolling down the hill, with distinct phenotypes as basins and differentiation pathways as valleys. Since, at a molecular level, cell differentiation arises from interactions among the genes, a mathematical definition for the Waddington landscape can, in principle, be obtained by studying the gene regulatory networks. For eukaryotes, gene regulation is inextricably and intimately linked to histone modifications. However, the impact of such modifications on both landscape topography and stability of attractor states is not fully understood. In this work, we introduced a minimal kinetic model for gene regulation that combines the impact of both histone modifications and transcription factors. We further developed an approximation scheme based on variational principles to solve the corresponding master equation in a second quantized framework. By analyzing the steady-state solutions at various parameter regimes, we found that histone modification kinetics can significantly alter the behavior of a genetic network, resulting in qualitative changes in gene expression profiles. The emerging epigenetic landscape captures the delicate interplay between transcription factors and histone modifications in driving cell-fate decisions.

The Notch ligand, Delta-1, inhibits the differentiation of monocytes into macrophages but permits their differentiation into dendritic cells

Blood ◽  
2001 ◽  
Vol 98 (5) ◽  
pp. 1402-1407 ◽  
Author(s):  
Kohshi Ohishi ◽  
Barbara Varnum-Finney ◽  
Rita E. Serda ◽  
Claudio Anasetti ◽  
Irwin D. Bernstein
Keyword(s):  
Dendritic Cells ◽  
Notch Signaling ◽  
Cell Fate ◽  
Interleukin 4 ◽  
Cellular Interactions ◽  
Blood Monocytes ◽  
Notch Ligand ◽  
Cell Fate Decisions ◽  
Gm Csf ◽  
Tnf Α

Notch-mediated cellular interactions are known to regulate cell fate decisions in various developmental systems. A previous report indicated that monocytes express relatively high amounts of Notch-1 and Notch-2 and that the immobilized extracellular domain of the Notch ligand, Delta-1 (Deltaext-myc), induces apoptosis in peripheral blood monocytes cultured with macrophage colony-stimulating factor (M-CSF), but not granulocyte-macrophage CSF (GM-CSF). The present study determined the effect of Notch signaling on monocyte differentiation into macrophages and dendritic cells. Results showed that immobilized Deltaext-myc inhibited differentiation of monocytes into mature macrophages (CD1a+/−CD14+/− CD64+) with GM-CSF. However, Deltaext-myc permitted differentiation into immature dendritic cells (CD1a+CD14−CD64−) with GM-CSF and interleukin 4 (IL-4), and further differentiation into mature dendritic cells (CD1a+CD83+) with GM-CSF, IL-4, and tumor necrosis factor-α (TNF-α). Notch signaling affected the differentiation of CD1a−CD14+macrophage/dendritic cell precursors derived in vitro from CD34+ cells. With GM-CSF and TNF-α, exposure to Deltaext-myc increased the proportion of precursors that differentiated into CD1a+CD14− dendritic cells (51% in the presence of Deltaext-myc versus 10% in control cultures), whereas a decreased proportion differentiated into CD1a−CD14+ macrophages (6% versus 65%). These data indicate a role for Notch signaling in regulating cell fate decisions by bipotent macrophage/dendritic precursors.

Nox4 mediates angiotensin II-induced activation of Akt/protein kinase B in mesangial cells

2003 ◽  
Vol 285 (2) ◽  
pp. F219-F229 ◽  
Author(s):  
Yves Gorin ◽  
Jill M. Ricono ◽  
Nam-Ho Kim ◽  
Basant Bhandari ◽  
Goutam Ghosh Choudhury ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Protein Kinase ◽  
Nadph Oxidase ◽  
Mesangial Cells ◽  
Protein Kinase B ◽  
Small Gtpase ◽  
Dominant Negative ◽  
Ros Generation ◽  
Ang Ii ◽  
Phagocyte Nadph Oxidase

ANG II induces protein synthesis through the serine-threonine kinase Akt/protein kinase B (PKB) in mesangial cells (MCs). The mechanism(s) of activation of Akt/PKB particularly by G protein-coupled receptors, however, is not well characterized. We explored the role of the small GTPase Rac1, a component of the phagocyte NADPH oxidase, and the gp91 phox homologue Nox4/Renox in this signaling pathway. ANG II causes rapid activation of Rac1, an effect abrogated by phospholipase A2 inhibition and mimicked by arachidonic acid (AA). Northern blot analysis revealed high levels of Nox4 transcript in MCs and transfection with antisense (AS) oligonucleotides for Nox4 markedly decreased NADPH-dependent reactive oxygen species (ROS)-producing activity. Dominant negative Rac1 (N17Rac1) as well as AS Nox4 inhibited ROS generation in response to ANG II and AA, whereas constitutively active Rac1 stimulated ROS formation. Moreover, N17Rac1 blocked stimulation of NADPH oxidase activity by AA. N17Rac1 or AS Nox4 abolished ANG II- or AA-induced activation of the hypertrophic kinase Akt/PKB. In addition, AS Nox4 inhibited ANG II-induced protein synthesis. These data provide the first evidence that activation by AA of a Rac1-regulated, Nox4-based NAD(P)H oxidase and subsequent generation of ROS mediate the effect of ANG II on Akt/PKB activation and protein synthesis in MCs.

scholarly journals The Impact of Epigenetic Signatures on Amniotic Fluid Stem Cell Fate

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Daniela Di Tizio ◽  
Alessandra Di Serafino ◽  
Prabin Upadhyaya ◽  
Luca Sorino ◽  
Liborio Stuppia ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Stem Cells ◽  
Amniotic Fluid ◽  
Cell Fate ◽  
Histone Modifications ◽  
Current Evidence ◽  
Cell Fate Decisions ◽  
Small Noncoding Rnas ◽  
Tight Correlation ◽  
The Impact

Epigenetic modifications play a significant role in determining the fate of stem cells and in directing the differentiation into multiple lineages. Current evidence indicates that mechanisms involved in chromatin regulation are essential for maintaining stable cell identities. There is a tight correlation among DNA methylation, histone modifications, and small noncoding RNAs during the epigenetic control of stem cells’ differentiation; however, to date, the precise mechanism is still not clear. In this context, amniotic fluid stem cells (AFSCs) represent an interesting model due to their unique features and the possible advantages of their use in regenerative medicine. Recent studies have elucidated epigenetic profiles involved in AFSCs’ lineage commitment and differentiation. In order to use these cells effectively for therapeutic purposes, it is necessary to understand the basis of multiple-lineage potential and elaborate in detail how cell fate decisions are made and memorized. The present review summarizes the most recent findings on epigenetic mechanisms of AFSCs with a focus on DNA methylation, histone modifications, and microRNAs (miRNAs) and addresses how their unique signatures contribute to lineage-specific differentiation.

scholarly journals NOX3, a Superoxide-generating NADPH Oxidase of the Inner Ear

2004 ◽  
Vol 279 (44) ◽  
pp. 46065-46072 ◽  
Author(s):  
Botond Bánfi ◽  
Brigitte Malgrange ◽  
Judit Knisz ◽  
Klaus Steger ◽  
Michel Dubois-Dauphin ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Nadph Oxidase ◽  
Inner Ear ◽  
Superoxide Production ◽  
Ros Generation ◽  
Human Embryonic Kidney ◽  
Phagocyte Nadph Oxidase ◽  
293 Cells ◽  
Dual Domain ◽  
Balance Problems

Reactive oxygen species (ROS) play a major role in drug-, noise-, and age-dependent hearing loss, but the source of ROS in the inner ear remains largely unknown. Herein, we demonstrate that NADPH oxidase (NOX) 3, a member of the NOX/dual domain oxidase family of NADPH oxidases, is highly expressed in specific portions of the inner ear. As assessed by real-time PCR, NOX3 mRNA expression in the inner ear is at least 50-fold higher than in any other tissues where its expression has been observed (e.g.fetal kidney, brain, skull). Microdissection andin situhybridization studies demonstrated that NOX3 is localized to the vestibular and cochlear sensory epithelia and to the spiral ganglions. Transfection of human embryonic kidney 293 cells with NOX3 revealed that it generates low levels of ROS on its own but produces high levels of ROS upon co-expression with cytoplasmic NOX subunits. NOX3-dependent superoxide production required a stimulus in the absence of subunits and upon co-expression with phagocyte NADPH oxidase subunits p47phoxand p67phox, but it was stimulus-independent upon co-expression with colon NADPH oxidase subunits NOX organizer 1 and NOX activator 1. Pre-incubation of NOX3-transfected human embryonic kidney 293 cells with the ototoxic drug cisplatin markedly enhanced superoxide production, in both the presence and the absence of subunits. Our data suggest that NOX3 is a relevant source of ROS generation in the cochlear and vestibular systems and that NOX3-dependent ROS generation might contribute to hearing loss and balance problems in response to ototoxic drugs.

scholarly journals NADPH oxidase controls phagosomal pH and antigen cross-presentation in human dendritic cells

Blood ◽  
2008 ◽  
Vol 112 (12) ◽  
pp. 4712-4722 ◽  
Author(s):  
Adriana R. Mantegazza ◽  
Ariel Savina ◽  
Mónica Vermeulen ◽  
Laura Pérez ◽  
Jorge Geffner ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Nadph Oxidase ◽  
Tumor Antigens ◽  
Phagocytic Cells ◽  
Cross Presentation ◽  
Phagocyte Nadph Oxidase ◽  
Healthy Donors ◽  
Endosomal Ph ◽  
Human Dendritic Cells ◽  
Model Tumor

Abstract The phagocyte NADPH oxidase (NOX2) is critical for the bactericidal activity of phagocytic cells and plays a major role in innate immunity. We showed recently that NOX2 activity in mouse dendritic cells (DCs) prevents acidification of phagosomes, promoting antigen cross-presentation. Inorder to investigate the role of NOX2 in the regulation of the phagosomal pH in human DCs, we analyzed the production of reactive oxygen species (ROS) and the phagosomal/endosomal pH in monocyte-derived DCs and macrophages (MØs) from healthy donors or patients with chronic granulomatous disease (CGD). As expected, we found that human MØs acidify their phagosomes more efficiently than human DCs. Accordingly, the expression of the vacuolar proton ATPase (V-H+-ATPase) was higher in MØs than in DCs. Phagosomal ROS production, however, was also higher in MØs than in DCs, due to higher levels of gp91phox expression and recruitment to phagosomes. In contrast, in the absence of active NOX2, the phagosomal and endosomal pH decreased. Both in the presence of a NOX2 inhibitor and in DCs derived from patients with CGD, the cross-presentation of 2 model tumor antigens was impaired. We conclude that NOX2 activity participates in the regulation of the phagosomal and endosomal pH in human DCs, and is required for efficient antigen cross-presentation.

Dynamic Expression of Id2 Determines Cell Fate Decisions in Multipotent Hematopoietic Cells

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2369-2369
Author(s):  
Jonathan R Keller ◽  
Ming Ji ◽  
Huajie Li ◽  
Serguei V Kozlov ◽  
Lino Tessarollo ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Mouse Model ◽  
Nk Cells ◽  
Cell Fate ◽  
Expression Profile ◽  
Differentiation Potential ◽  
Self Renewal ◽  
Developmental Potential ◽  
Cell Fate Decisions ◽  
Lymphoid Development

Abstract Abstract 2369 Inhibitor of DNA binding protein-2 (Id2) is a member of the helix-loop-helix family of transcriptional regulators that is required for the normal development of natural killer (NK) cells, dendritic cells, B cells and erythrocytes. However, little is known about the expression and function of Id2 in hematopoietic stem and progenitor cells (HSPC). Recent evidence suggests that cell fate is resolved in HSPC by regulating the levels transcription factor expression. Therefore, to determine if Id2 functions in cell fate decisions, and in which progenitor populations these decisions are made, we generated an Id2-EYFP reporter mouse model and validated that EYFP accurately reflected Id2 expression. Using this model we mapped Id2 expression levels in purified HSPC and their differentiated progeny. Id2 is highly expressed in differentiated neutrophils, dendritic cells and NK cells, but is suppressed during erythroid development. Id2 expression is dynamically regulated during lymphoid development, with high levels of Id2 expression in lymphoid progenitors that are down regulated during the early stages of T cell (DN2-DN4) and B cell (Pre-B) differentiation. Id2 is then up-regulated and highly expressed in CD4+CD8+ and single positive CD4 and CD8 thymocytes, suggesting that Id2 may have novel functions in differentiated T cells and in neutrophils. Id2 is expressed in HSC and multi-potent progenitors (MPP), is decreased in common myeloid progenitors (CMP), and further decreased in myeloid/erythroid progenitors (MEP), but increased in granulocyte/macrophage progenitors (GMP). We also observed a range of Id2 expression within purified HSPC, suggesting that the levels of Id2 expression in purified HSC, MPP and CMP may correlate with potential of these progenitors for myeloid, erythroid and lymphoid development. To investigate this, CMP Id2-hi and CMP-Id2-low expressing cells were sorted and evaluated for differentiation potential in vitro. CMP-Id2-hi cells showed greatly increased myeloid developmental potential compared to the CMP-Id2-low cells as indicated by flow cytometry and growth in soft agar. Gene expression profiles confirmed these results and showed that the CMP-Id2-hi cell expression profile correlated with the expression profile of GMP, while the CMP-Id2-lo cells showed an expression profile that resembled MEP. Based on these observations we anticipate that MPP-Id2-hi and MPP-Id2-lo cells will show differences in myeloid and lymphoid potential. The expression of Id2 in primitive HSPC suggested that Id2 may be required for the maintenance and fate of HSC. Using the Id2−/− mouse model, we discovered that Id2−/− bone marrow cells have impaired ability to rescue mice after serial transplantation, suggesting that Id2 is required for HSC self-renewal. Competitive repopulation assays showed that Id2−/− HSC have diminished repopulation potential. Thus, these data suggest that Id2 is required for the self-renewal of HSC, and that changes in the levels of Id2 expression are associated with cell fate determination of HSPC. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Oral intake of lipopolysaccharide regulates toll-like receptor 4-dependent granulopoiesis

2020 ◽  
Vol 245 (14) ◽  
pp. 1254-1259
Author(s):  
Melanie Märklin ◽  
Stefanie Bugl ◽  
Stefan Wirths ◽  
Julia-Stefanie Frick ◽  
Martin R Müller ◽  
...  
Keyword(s):  
Steady State ◽  
Cell Fate ◽  
Progenitor Cell ◽  
Oral Intake ◽  
Innate Immune ◽  
Toll Like Receptor ◽  
Gastrointestinal Microbiome ◽  
Hematopoietic Stem ◽  
Cell Fate Decisions ◽  
The Impact

While neutrophil production in emergency states has been extensively studied, regulation of neutrophil homeostasis in the steady-state remained incompletely understood. We have shown that innate immune receptor toll-like receptor (TLR)4 and downstream TIR-domain-containing adapter-inducing interferon-β (TRIF) are indispensable for the generation of a granulocyte-colony stimulating factor (G-CSF)-dependent regulatory feedback loop upon antibody-induced neutropenia. These findings demonstrated that steady-state granulopoiesis is a demand-driven process, which may rely on differential triggering of innate immune receptors by microbial cell wall constituents such as lipopolysaccharide. Herein, we present further evidence on underlying mechanisms: oral intake of highly endotoxic lipopolysaccharide, but not TLR-antagonistic lipopolysaccharide derived from Rhodobacter sphaeroides, induces hematopoietic stem and progenitor cell fate decisions toward the neutrophil lineage independent of G-CSF. TLR4 has been identified as the indispensable sensor for oral lipopolysaccharide-modulated steady-state granulopoiesis. These results have important implications: food lipopolysaccharide content or the composition of the gastrointestinal microbiome may be strongly underrated as determinants of peripheral blood neutrophil levels. Both neutrophilia and neutropenia are associated with drastically worse outcomes in epidemiological studies of the general population as well as in diseased states. Impact statement In our present study, we investigated the impact of LPS on neutrophil homeostasis and found that oral intake is sufficient to induce hematopoietic stem and progenitor cell fate decisions towards the neutrophil lineage independent of G-CSF. In addition, TLR4 has been identified as the indispensable sensor for oral LPS-modulated steady-state granulopoiesis. We provide evidence that the gastrointestinal microbiome is critical for neutrophil homeostasis, which has implications for patients being treated with chemotherapy or antimicrobial therapy, since both are significantly influencing the composition of the intestinal microbiome.

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