Whole brain transcriptome of wild-type or Nav1.8CreROSA26DTA mice upon LPS sepsis
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PROVIDER: PRJNA724707 | ENA |
REPOSITORIES: ENA
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Project description:To check changes in transcriptome in whole brain upon LPS sepsis, mice were injected with PBS or LPS and gene expression was analyzed. Nav1.8CreROSA26DTA mice lack Nav1.8-positive nociceptor.
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Project description:Studies have shown that stimulation of Mesenchymal stem cells (MSCs) with biophysical or biochemical cues could influence the contents and biological activities of subsequent MSC-derived exosomes. However, the underlying mechanisms have not been fully clarified. Here, we pretreated MSCs with lipopolysaccharide (LPS) and evaluated exosomes (LPS-Exo) therapeutic effects in sepsis. Analysis of exosomes activity revealed that LPS-Exo treatment improved sepsis to a greater extent than normal MSCs-derived exosomes (Exo). Further analysis revealed that LPS-Exo exert their protective effects mainly through RNA contents. Thus, we hypothesized that LPS preconditioning enhances the therapeutic efficacy of LPS-Exo in sepsis by altering miRNA expression profile.
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Project description:Among the diseases caused by Toll-like receptor 4 (TLR4) abnormal activation by bacterial endotoxin, sepsis is the most dangerous one. The reprogramming of macrophages plays a crucial role in orchestrating the pathogenesis of sepsis. However, the precise mechanism underlying TLR4 activation in macrophages remained incompletely understood. Our studies revealed that upon lipopolysaccharide (LPS) stimulation, CREB-binding protein (CBP) was recruited to the TLR4 signalosome complex and resulted in pronounced acetylation in the TIR domains of TLR4, Myeloid differentiation factor 88 (MyD88) and MyD88 adapter-like (MAL), which significantly enhanced the activation of the NF-κB signaling pathway and polarization of M1 macrophages. In sepsis patients, significantly elevated TLR4-TIR acetylation was detected in CD16+ monocytes combined with elevated expression of M1 macrophage markers and production of pro-inflammatory cytokines. In contrast, histone deacetylase 1 (HDAC1) served as a key deacetylase in the deacetylation of the TIR domain complex. The inhibition of HDAC1 accelerated sepsis-associated syndromes, while the inhibition of CBP alleviated this process. Overall, our findings highlighted the crucial role of TIR domain complex acetylation in the regulation of inflammatory immune response and suggested that the reversible acetylation of the complex emerged as a promising therapeutic target for M1 macrophages during the progression of sepsis.
2024-08-01 | PXD052433 | Pride
Project description:Blood monocytes serve as the first line of host defense and are equipped to recognize and respond to infection by triggering an immune-inflammatory response. While most information on these cells comes from in vitro studies in humans or in vivo studies in mice, little is known about monocytes under human disease conditions. We investigated the role of monocytes during sepsis and its resolution in humans. A transcriptomal and functional analysis of blood monocytes from patients during gram negative sepsis and at recovery was performed. Monocytes from sepsis patients showed upregulation of a large number of pro-inflammatory genes and cytokines/chemokines, consistent with an ongoing systemic inflammation. However, these cells showed impairment to ex vivo endotoxin (LPS) challenge, displaying a quantitative decrease in the number of LPS-inducible genes. Moreover, they downregulated the expression of several pro-inflammatory cytokine/chemokine genes, activation marker genes and transcription factors associated with monocyte/macrophage activation, upon ex vivo LPS stimulation. Functionally, they downregulated expression of inflammatory cytokines/chemokines and antigen presentation-related molecules and functions. In contrast, genes and functions related to phagocytosis, anti-microbial activity and tissue remodeling where remained unaffected or even enhanced . Collectively, our observations suggest a genetic and functional re-programming of these cells during human sepsis progression. Understanding the molecular mechanisms which regulate this re-programming will allow to devise strategies which could modulate the response of these cells and hence, disease progression. Blood monocytes from gram-negative sepsis patients during sepsis (Sepsis) and following their recovery (Recovery/Basal) as well as healthy donor (control) were isolated. Thereafter, these cells were treated ex vivo with or without LPS for 3h and analysed for transcriptomic study.
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Project description:Because the immune regulation in survivor after sepsis (an immune dysregulation from severe infection) might be applied for treatment, survivors and moribund mice after cecal liga-tion and puncture (CLP) and in vitro experiments on macrophages were explored. Most of the parameters in survivors (5-days post-CLP) were normalized, except for the slightly increase in alanine transaminase, IL-10, lipopolysaccharide (LPS) and gut leakage (FITC-dextran assay), with the enhanced adaptive immunity; serum immunoglobulin (using serum protein electrophoresis) and activated immune cells in spleens (flow cytometry analysis). Then, a clue to surviving sepsis may be effective innate immunity regulation by adaptive immune responses. Indeed, soluble heat aggregated immunoglobulin (sHA-Ig, a representative of immune complex) in LPS-activated macrophages reduced supernatant cytokines and down-regulated proteins in sev-eral processes (using proteomic analysis). As a proof of concept, intravenous immunoglobulin (IVIG) attenuated sepsis severity in CLP mice as evaluated by serum creatinine, ALT, serum cy-tokines, spleen apoptosis (24 h post-CLP) and 48 h survival analysis. In conclusion, immuno-globulin may play a role in sepsis immune hyper-responsiveness. Despite the debate over IVIG's use in sepsis, adequate selection criteria for sepsis patients who may benefit the most from IVIG could lead to an increase use of this clinically viable treatment.
2022-02-22 | PXD027471 | Pride
Project description:Moringa Isothiocyanate-1 (MIC-1) purified from moringa (Moringa oleifera Lam) seed extract (MSE) has been previously proved to modulate anti-inflammatory and antioxidant activities. However, the molecular mechanism remains poorly understood, particularly nothing is known about its effect on Lipopolysaccharide (LPS) induced sepsis/inflammation. Hence, we investigated whether MIC-1 can decrease acute inflammation in the LPS-induced acute inflammation/sepsis model in mice. Mice were treated orally with MIC-1 for three days before the intraperitoneal injection of LPS. MIC-1 treatment resulted in a dramatic improvement in the histopathological signs of inflammation in the liver, kidney, spleen, and colon and a significant reduction of the LPS-induced sepsis. Moreover, MIC-1 treatment significantly reduced the expression of inflammatory markers in all these organs. We also performed transcriptome analysis in vitro and in vivo in LPS induced macrophages and liver with/without MIC-1 treatment. Interestingly, there is an upregulation of inflammatory/immune response genes in LPS induced macrophages/liver, and there is downregulation of same set of genes after treating with MIC-1. Our results together indicate that MIC-1 reduces sepsis/inflammation through NF-κB and Nrf2 mediated anti-inflammatory/antioxidant signaling pathways. Research has demonstrated that chronic low-grade tissue inflammation and oxidative stress are essential factors in the development of metabolic disorders. Therefore, MIC-1 could be a new natural therapeutic strategy to treat metabolic syndrome.
2021-04-07 | GSE155738 | GEO
Project description:The purpose of this study is to examine the transcriptomic profiles (RNAseq) of post-mortem brain tissue samples from patients who have died of sepsis compared to non-sepsis controls using two analytic approaches. Tissue samples originated from the Adult Changes in Thought study (ACT) brain bank. In order to determine cause of death, hospital charts for 89 ACT subjects who died while hospitalized were reviewed using a structured instrument for diagnosis of sepsis. RNA was extracted from 24 post-mortem parietal cortex tissue samples. RNA sequencing was performed on the 24 samples using Illumina's Hi-Seq platform. Raw data was exported, pre-processed, and analyzed by two methods, differential expression and weighted gene co-expression network analysis (WGCNA). 176 genes were differentially expressed with fold change of > 1.5 and adjusted p < 0.5. The top differentially expressed genes were immune-related. WGCNA reveled 6 modules were significantly correlated with sepsis. Significant nodules were enriched in terms associated with innate immunity, cytokines, DAMPs, synaptic function, ion channel function, neuronal growth, and T-cell signalling among others. These data suggest sepsis is associated with specific transcriptional responses in the human brain. These results provide support for previously identified targets as well as provide evidence to suggest investigation into new targets for mechanistic exploration of sepsis-associated brain injury.
2019-11-26 | GSE135838 | GEO
Project description:Among the diseases caused by Toll-like receptor 4 (TLR4) abnormal activation by bacterial endotoxin, sepsis is the most dangerous one. The reprogramming of macrophages plays a crucial role in orchestrating the pathogenesis of sepsis. However, the precise mechanism underlying TLR4 activation in macrophages remained incompletely understood. Our studies revealed that upon lipopolysaccharide (LPS) stimulation, CREB-binding protein (CBP) was recruited to the TLR4 signalosome complex and resulted in pronounced acetylation in the TIR domains of TLR4, Myeloid differentiation factor 88 (MyD88) and MyD88 adapter-like (MAL), which significantly enhanced the activation of the NF-κB signaling pathway and polarization of M1 macrophages. In sepsis patients, significantly elevated TLR4-TIR acetylation was detected in CD16+ monocytes combined with elevated expression of M1 macrophage markers and production of pro-inflammatory cytokines. In contrast, histone deacetylase 1 (HDAC1) served as a key deacetylase in the deacetylation of the TIR domain complex. The inhibition of HDAC1 accelerated sepsis-associated syndromes, while the inhibition of CBP alleviated this process. Overall, our findings highlighted the crucial role of TIR domain complex acetylation in the regulation of inflammatory immune response and suggested that the reversible acetylation of the complex emerged as a promising therapeutic target for M1 macrophages during the progression of sepsis.
2024-08-01 | GSE268406 | GEO
Project description:Among the diseases caused by Toll-like receptor 4 (TLR4) abnormal activation by bacterial endotoxin, sepsis is the most dangerous one. The reprogramming of macrophages plays a crucial role in orchestrating the pathogenesis of sepsis. However, the precise mechanism underlying TLR4 activation in macrophages remained incompletely understood. Our studies revealed that upon lipopolysaccharide (LPS) stimulation, CREB-binding protein (CBP) was recruited to the TLR4 signalosome complex and resulted in pronounced acetylation in the TIR domains of TLR4, Myeloid differentiation factor 88 (MyD88) and MyD88 adapter-like (MAL), which significantly enhanced the activation of the NF-κB signaling pathway and polarization of M1 macrophages. In sepsis patients, significantly elevated TLR4-TIR acetylation was detected in CD16+ monocytes combined with elevated expression of M1 macrophage markers and production of pro-inflammatory cytokines. In contrast, histone deacetylase 1 (HDAC1) served as a key deacetylase in the deacetylation of the TIR domain complex. The inhibition of HDAC1 accelerated sepsis-associated syndromes, while the inhibition of CBP alleviated this process. Overall, our findings highlighted the crucial role of TIR domain complex acetylation in the regulation of inflammatory immune response and suggested that the reversible acetylation of the complex emerged as a promising therapeutic target for M1 macrophages during the progression of sepsis.
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