| 1. |
- 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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| 2. |
- 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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| 3. |
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| 4. |
- 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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| 6. |
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| 7. |
- Sternberg-Simon, M., et al.
(författare)
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Natural killer cell inhibitory receptor expression in humans and mice : A closer look
- 2013
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 4:March, s. 65-
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Tidskriftsartikel (refereegranskat)abstract
- The Natural Killer (NK) cell population is composed of subsets of varying sizes expressing different combinations of inhibitory receptors for MHC class I molecules. Genes within the NK gene complex, including the inhibitory receptors themselves, seem to be the primary intrinsic regulators of inhibitory receptor expression, but the MHC class I background is an additional Modulating factor. In this paper, we have performed a parallel study of the inhibitory receptor repertoire in inbred mice of the C57Bl/6 background and in a cohort of 44 humans. Deviations of subset frequencies from the "product rule (PR)," i.e., differences between observed and expected frequencies of NK cells, were used to identify MHC-independent and MHC-dependent control of receptor expression frequencies. Some deviations from the PR were similar in mice and humans, such as the decreased presence of NK cell subset lacking inhibitory receptors. Others were different, including a role for NKG2A in determining over- or under-representation of specific subsets in humans but not in mice. Thus, while human and murine inhibitory receptor repertoires differed in details, there may also be shared principles governing NK cell repertoire formation in these two species.
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