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- Almyroudis, Nikolaos G., et al.
(författare)
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NETosis and NADPH oxidase : at the intersection of host defense, inflammation, and injury
- 2013
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 4
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Forskningsöversikt (refereegranskat)abstract
- Neutrophils are armed with both oxidant-dependent and -independent pathways for killing pathogens. Activation of the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase constitutes an emergency response to infectious threat and results in the generation of antimicrobial reactive oxidants. In addition, NADPH oxidase activation in neutrophils is linked to activation of granular proteases and generation of neutrophil extracellular traps (NETs). NETosis involves the release of nuclear and granular components that can target extracellular pathogens. NETosis is activated during microbial threat and in certain conditions mimicking sepsis, and can result in both augmented host defense and inflammatory injury. In contrast, apoptosis, the physiological form of neutrophil death, not only leads to non-inflammatory cell death but also contributes to alleviate inflammation. Although there are significant gaps in knowledge regarding the specific contribution of NETs to host defense, we speculate that the coordinated activation of NADPH oxidase and NETosis maximizes microbial killing. Work in engineered mice and limited patient experience point to varying susceptibility of bacterial and fungal pathogens to NADPH oxidase versus NET constituents. Since reactive oxidants and NET constituents can injure host tissue, it is important that these pathways be tightly regulated. Recent work supports a role for NETosis in both acute lung injury and in autoimmunity. Knowledge gained about mechanisms that modulate NETosis may lead to novel therapeutic approaches to limit inflammation-associated injury.
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| 4. |
- Christenson, Karin, et al.
(författare)
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Endogenous Acute Phase Serum Amyloid A Lacks Pro-Inflammatory Activity, Contrasting the Two Recombinant Variants That Activate Human Neutrophils through Different Receptors.
- 2013
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Ingår i: Frontiers in immunology. - : Frontiers Media SA. - 1664-3224. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Most notable among the acute phase proteins is serum amyloid A (SAA), levels of which can increase 1000-fold during infections, aseptic inflammation, and/or trauma. Chronically elevated SAA levels are associated with a wide variety of pathological conditions, including obesity and rheumatic diseases. Using a recombinant hybrid of the two human SAA isoforms (SAA1 and 2) that does not exist in vivo, numerous in vitro studies have given rise to the notion that acute phase SAA is a pro-inflammatory molecule with cytokine-like properties. It is however unclear whether endogenous acute phase SAA per se mediates pro-inflammatory effects. We tested this in samples from patients with inflammatory arthritis and in a transgenic mouse model that expresses human SAA1. Endogenous human SAA did not drive production of pro-inflammatory IL-8/KC in either of these settings. Human neutrophils derived from arthritis patients displayed no signs of activation, despite being exposed to severely elevated SAA levels in circulation, and SAA-rich sera also failed to activate cells in vitro. In contrast, two recombinant SAA variants (the hybrid SAA and SAA1) both activated human neutrophils, inducing L-selectin shedding, production of reactive oxygen species, and production of IL-8. The hybrid SAA was approximately 100-fold more potent than recombinant SAA1. Recombinant hybrid SAA and SAA1 activated neutrophils through different receptors, with recombinant SAA1 being a ligand for formyl peptide receptor 2 (FPR2). We conclude that even though recombinant SAAs can be valuable tools for studying neutrophil activation, they do not reflect the nature of the endogenous protein.
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- Esaki, Shankar, et al.
(författare)
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Upregulation of Inhibitory Molecules in T Cells is Associated with Altered Functions of Dendritic Cells by HIV-1 and Activation of the P38MAPK/STAT3 Signaling Pathways
- 2013
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 4
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- HIV-1 reportedly augments the expression of certain negative costimulatory and inhibitory molecules on T cells, leading to immune impairment. The signaling mechanisms underlying the induction of suppressor molecules and subsequent onset of T-cell impairment in HIV infection remain ambiguous. Our experiments with both autologous and allogeneic T cells exposed to HIV-pulsed dendritic cells showed increased expression of LAG-3, TIM-3, CD160 CTLA-4, TRAIL, and certain suppression-associated transcription factors, namely Blimp-1, DTX1 and FoxP3, whose recruitments were closely regulated by P38MAPK/STAT3 signal transduction pathways. Blockade of P38MAPK/STAT3 significantly decreased the expression of the inhibitory molecules studied and significantly restored T-cell proliferation. The P38MAPK/STAT3 proteins had a higher degree of phosphorylation in the HIV-1-primed cells. We also found that IL-6 and IL-10, and certain other growth factors commonly known to activate STAT3 signaling events were not responsible for STAT3 activation. Blockade of viral CD4 binding and fusion with DCs significantly reduced the negative effects DCs imposed on primed T cells. We concluded that HIV-1 negatively modulate DC functions, causing the activation of the P38MAPK/STAT3 pathway in T cells, leading to recruitment of inhibitory molecules and subsequent onset of T-cell impairment.
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| 7. |
- Forslund, E., et al.
(författare)
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Novel microchip-based tools facilitating live cell imaging and assessment of functional heterogeneity within NK cell populations
- 2012
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 3:OCT, s. 300-
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Tidskriftsartikel (refereegranskat)abstract
- Each individual has a heterogeneous pool of NK cells consisting of cells that may be specialized towards specific functional responses such as secretion of cytokines or killing of tumor cells. Many conventional methods are not fit to characterize heterogeneous populations as they measure the average response of all cells. Thus, there is a need for experimental platforms that provide single cell resolution. In addition, there are transient and stochastic variations in functional responses at the single cell level, calling for methods that allow studies of many events over extended periods of time. This paper presents a versatile microchip platform enabling long-term microscopic studies of individual NK cells interacting with target cells. Each microchip contains an array of microwells, optimized for medium or high-resolution time-lapse imaging of single or multiple NK and target cells, or for screening of thousands of isolated NK-target cell interactions. Individual NK cells confined with target cells in small microwells is a suitable setup for high-content screening and rapid assessment of heterogeneity within populations, while microwells of larger dimensions are appropriate for studies of NK cell migration and sequential interactions with multiple target cells. By combining the chip technology with ultrasonic manipulation, NK and target cells can be forced to interact and positioned with high spatial accuracy within individual microwells.This setup effectively and synchronously creates NK-target conjugates at hundreds of parallel positions in the microchip. Thus, this facilitates assessment of temporal aspects of NK-target cell interactions, e.g., conjugation, immune synapse formation, and cytotoxic events.The microchip platform presented here can be used to effectively address questions related to fundamental functions of NK cells that can lead to better understanding of how the behavior of individual cells add up to give a functional response at the population level.
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| 8. |
- Hosseinzadeh, Ava, et al.
(författare)
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Stable Redox-Cycling Nitroxide Tempol Inhibits NET Formation
- 2012
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Ingår i: Frontiers in Immunology. - : Frontiers Media S.A. - 1664-3224. ; 3
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Tidskriftsartikel (refereegranskat)abstract
- To prevent the spread of pathogens neutrophils as the first line of defense are able to release Neutrophil Extracellular Traps (NETs), a recently discovered form of immune response. Reactive oxygen species (ROS) have been shown to be essential for many different induction routes of NET formation. Therefore, pharmacological inhibition of ROS generation has implications for research and medicine related to NETs. The application of diphenylene iodonium (DPI), an inhibitor of NADPH oxidase activity, is limited due to its toxicity to host cells as well as microbes. Therefore, we investigated the effect of 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (Tempol) a membrane-permeable radical scavenger on NET formation triggered by phorbol esters and Candida albicans. We quantified the amount of NETs with two complementary methods, using a microscopic analysis and an online fluorescence-based assay. In line with removal of ROS, Tempol reduced the amount of NET formation by neutrophils challenged with those stimuli significantly. Since Tempol efficiently blocks NET formation in vitro, it might be promising to test the effect of Tempol in experimental models of disorders in which NETs probably have hazardous effects.
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