Nitrosothiols in the Immune System: Signaling and Protection

Hernansanz-Agustín, Pablo; Izquierdo-Álvarez, Alicia; García-Ortiz, Almudena; Ibiza, Sales; Serrador, Juan Manuel; Martínez‐Ruiz, Antonio

doi:10.1089/ars.2012.4765

Cited by 44 publications

(39 citation statements)

References 205 publications

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“…The mechanism by which pGSN may act includes priming or activating macrophage NOS3 (28), which can then contribute to improved killing of ingested bacteria by direct bactericidal mechanisms, either alone or in combination with superoxide (10); pGSN might also act to mediate salutary intracellular signaling events (14). Additional pathways are also suggested by the observation that pGSN caused enhanced internalization of bacteria, an effect not observed in the presence of other activators of macrophage NOS3 (28).…”

Section: Discussionmentioning

confidence: 99%

Plasma gelsolin improves lung host defense against pneumonia by enhancing macrophage NOS3 function

Yang

Chiou

Stossel

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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Section: Discussionmentioning

confidence: 99%

Plasma gelsolin improves lung host defense against pneumonia by enhancing macrophage NOS3 function

Yang

Chiou

Stossel

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…[30][31][32] Similar to phosphorylation, S-nitrosylation of proteins can switch biological signals on and off and has been reported to function for both innate and adaptive immunity. 49 In human B-and T-cell lines, S-nitrosylation blocks activation of caspase-3.…”

Section: Discussionmentioning

confidence: 99%

IL-15 maintains T-cell survival via S-nitrosylation-mediated inhibition of caspase-3

et al. 2014

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Caspase activity is critical for both T-cell survival and death. However, little is known regarding what determines caspase activity in cycling T cells. Interleukin (IL)-2 and IL-15 confer very different susceptibilities to T-cell death. We therefore considered that IL-2 and IL-15 differentially regulate caspase activity to influence T-cell survival. We observed that IL-2-cultured primary murine effector T cells manifested elevated levels of caspase-3 activity compared with IL-15-cultured T cells. T cell receptor (TCR) restimulation further increased caspase activity and induced considerable cell death in IL-2-cultured T cells, but provoked only a minimal increase of caspase activity and cell death in IL-15-cultured T cells. IL-2 sensitization to cell death was caspase-3 mediated. Interestingly, increased active caspase-3 levels with IL-2 were independent of active initiator caspase-8 and caspase-9 that were similar with IL-2 and IL-15. Rather, caspase-3 activity was inhibited by posttranslational S-nitrosylation in IL-15-cultured T cells, but not in the presence of IL-2. This paralleled increased reactive nitrogen and oxygen species with IL-15 and reduced glycolysis. Taken together, these data suggest that the metabolic state conferred by IL-15 inhibits T-cell apoptosis in part by maintaining low levels of active caspase-3 via S-nitrosylation.

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“…Hypernitrosylation may downregulate intracellular signaling pathways including NF-B and the TLR4 complex and thus may have restorative effects [56]. IgM-mediated autoimmune responses directed to oxidative specific epitopes are part of natural autoimmune responses that actually have restorative effects [57].…”

Section: Gaps and Required Improvements: New Treatmentsmentioning

confidence: 99%

Toward Omics-Based, Systems Biomedicine, and Path and Drug Discovery Methodologies for Depression-Inflammation Research

et al. 2015

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Meta-analyses confirm that depression is accompanied by signs of inflammation including increased levels of acute phase proteins, e.g. C-reactive protein, and pro-inflammatory cytokines, e.g. interleukin-6. Supporting the translational significance of this, a meta-analysis showed that anti-inflammatory drugs may have antidepressant effects. Here we argue that inflammation and depression research needs to get onto a new track. Firstly, the choice of inflammatory biomarkers in depression research was often too selective and did not consider the broader pathways.Secondly, although mild inflammatory responses are present in depression, other immune-related pathways cannot be disregarded as new drug targets, e.g. activation of cell-mediated immunity, oxidative and nitrosative stress (O&NS) pathways, autoimmune responses, bacterial translocation, activation of the Toll-like Receptor and neuroprogressive pathways. Thirdly, antiinflammatory treatments are sometimes used without full understanding of their effects on the broader pathways underpinning depression. Since many of the activated immune-inflammatory pathways in depression actually confer protection against an overzealous inflammatory response, targeting these pathways may result in unpredictable and unwanted results. Furthermore, this paper discusses the required improvements in research strategy, i.e. path and drug discovery processes, omics-based techniques and systems biomedicine methodologies. Firstly, novel methods should be employed to examine the intracellular networks that control and modulate the immune, O&NS and neuroprogressive pathways using omics-based assays, including genomics, transcriptomics, proteomics, metabolomics, epigenomics and microbiomics. Secondly, systems biomedicine analyses are essential to unravel the complex interactions between these cellular 4 networks, pathways and the multifactorial trigger factors and to delineate new drug targets in the cellular networks or pathways. Drug discovery processes should delineate new drugs targeting the intracellular networks and immune-related pathways.

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Nitrosothiols in the Immune System: Signaling and Protection

Cited by 44 publications

References 205 publications

Plasma gelsolin improves lung host defense against pneumonia by enhancing macrophage NOS3 function

Plasma gelsolin improves lung host defense against pneumonia by enhancing macrophage NOS3 function

IL-15 maintains T-cell survival via S-nitrosylation-mediated inhibition of caspase-3

Toward Omics-Based, Systems Biomedicine, and Path and Drug Discovery Methodologies for Depression-Inflammation Research

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