21 research outputs found
Network Topologies and Dynamics Leading to Endotoxin Tolerance and Priming in Innate Immune Cells
The innate immune system, acting as the first line of host defense, senses
and adapts to foreign challenges through complex intracellular and
intercellular signaling networks. Endotoxin tolerance and priming elicited by
macrophages are classic examples of the complex adaptation of innate immune
cells. Upon repetitive exposures to different doses of bacterial endotoxin
(lipopolysaccharide) or other stimulants, macrophages show either suppressed or
augmented inflammatory responses compared to a single exposure to the
stimulant. Endotoxin tolerance and priming are critically involved in both
immune homeostasis and the pathogenesis of diverse inflammatory diseases.
However, the underlying molecular mechanisms are not well understood. By means
of a computational search through the parameter space of a coarse-grained
three-node network with a two-stage Metropolis sampling approach, we enumerated
all the network topologies that can generate priming or tolerance. We
discovered three major mechanisms for priming (pathway synergy, suppressor
deactivation, activator induction) and one for tolerance (inhibitor
persistence). These results not only explain existing experimental
observations, but also reveal intriguing test scenarios for future experimental
studies to clarify mechanisms of endotoxin priming and tolerance.Comment: 15 pages, 8 figures, submitte
Effect of Thymoquinone on Cytosolic pH and Na<sup>+</sup>/H<sup>+</sup> Exchanger Activity in Mouse Dendritic Cells
Thymoquinone from nutraceutical black cumin oil activates Neu4 sialidase in live macrophage, dendritic, and normal and type I sialidosis human fibroblast cells via GPCR Gαi proteins and matrix metalloproteinase-9
A chromatin activity-based chemoproteomic approach reveals a transcriptional repressome for gene-specific silencing
Immune cells develop endotoxin tolerance (ET) after prolonged stimulation. ET increases the level of a repression mark H3K9me2 in the transcriptional-silent chromatin specifically associated with pro-inflammatory genes. However, it is not clear what proteins are functionally involved in this process. Here we show that a novel chromatin activity based chemoproteomic (ChaC) approach can dissect the functional chromatin protein complexes that regulate ET-associated inflammation. Using UNC0638 that binds the enzymatically active H3K9-specific methyltransferase G9a/GLP, ChaC reveals that G9a is constitutively active at a G9a-dependent mega-dalton repressome in primary endotoxin-tolerant macrophages. G9a/GLP broadly impacts the ET-specific reprogramming of the histone code landscape, chromatin remodeling, and the activities of select transcription factors. We discover that the G9a-dependent epigenetic environment promotes the transcriptional repression activity of c-Myc for gene-specific co-regulation of chronic inflammation. ChaC may be also applicable to dissect other functional protein complexes in the context of phenotypic chromatin architectures
DNA Fragmentation, Caspase 3 and Prostate-Specific Antigen Genes Expression Induced by Arsenic, Cadmium, and Chromium on Nontumorigenic Human Prostate Cells
Anti-inflammatory Effect of Seeds and Callus of Nigella sativa L. Extracts on Mix Glial Cells with Regard to Their Thymoquinone Content
Metabolic dysfunction and immunometabolism in COVID-19 pathophysiology and therapeutics.
Epigenetic regulation of immune cell functions during post-septic immunosuppression
Studies in humans and animal models indicate that profound immunosuppression is one of the chronic consequences of severe sepsis. This immune dysfunction encompasses deficiencies in activation of cells in both the myeloid and lymphoid cell lineages. As a result, survivors of severe sepsis are at risk of succumbing to infections perpetrated by opportunistic pathogens that are normally controlled by a fully functioning immune system. Recent studies have indicated that epigenetic mechanisms may be one driving force behind this immunosuppression, through suppression of proinflammatory gene production and subsequent immune cell activation, proliferation and effector function. A better understanding of epigenetics and post-septic immunosuppression can improve our diagnostic tools and may be an important potential source of novel molecular targets for new therapies. This review will discuss important pathways of immune cell activation affected by severe sepsis, and highlight pathways of epigenetic regulation that may be involved in post-septic immunosuppression