Proteolytic disruption of renal endothelial glycocalyx in sepsis: Dexamethasone inhibition via TLR4/NF-κB/MMP axis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE309047 | GEO | 2025/10/01
REPOSITORIES: GEO
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Project description:Proteolytic disruption of renal endothelial glycocalyx in sepsis: Dexamethasone inhibition via TLR4/NF-κB/MMP axis
| PRJNA1333855 | ENA
Project description: Not available
| S-EPMC8850260 | biostudies-literature
Project description:Sepsis remains a major cause of death worldwide. The lung is particularly vulnerable, and sepsis‑induced acute lung injury (ALI) carries high mortality. Endothelial glycocalyx degradation is an early event that promotes vascular leakage and inflammation, but the upstream regulators of this process are poorly understood. Here we identify ubiquitin‑specific protease 2 (USP2) as a critical driver of pulmonary endothelial glycocalyx breakdown in sepsis. USP2 expression was markedly upregulated in lung endothelial cells of septic mice and in LPS-stimulated human endothelial cells. Endothelial‑specific Usp2 knockdown protected against cecal ligation and puncture (CLP)‑induced lung injury, vascular leakage, and glycocalyx degradation. Mechanistically, USP2 directly bound to mitochondrial carrier homolog 2 (MTCH2), an outer mitochondrial membrane protein, and removed K27‑linked ubiquitin chains at lysine 158, thereby stabilizing MTCH2. MTCH2 was required for USP2‑mediated downregulation of syndecan‑1 (SDC1), a core glycocalyx component, and its silencing rescued SDC1 levels in USP2‑overexpressing cells. Endothelial‑specific Mtch2 knockout mice phenocopied the protective effects of USP2 deficiency, including improved survival, preserved glycocalyx structure, and reduced inflammation. These findings uncover a USP2‑MTCH2 axis that links deubiquitination to glycocalyx integrity in the pulmonary endothelium during sepsis. Targeting this interaction may offer a new therapeutic strategy for septic ALI.
2026-06-30 | GSE336039 | 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 | PXD052433 | Pride
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.
2024-08-01 | GSE268405 | GEO
Project description: Not available
| S-EPMC12345315 | biostudies-literature
Project description:Group 3 innate lymphoid cells (ILC3s) are key regulators of mucosal immunity,yet their role in sepsis-associated colon injury remains unclear.Peripheral blood from healthy volunteers and septic patients was analyzed for ILC subset alterations.A LPS-induced murine sepsis model,combined with ILC3-deficient mice,was employed to assess ILC3 dynamic,function,metabolic features and impact on colon barrier interity using flow cytometry,histopathology,ELISA,RT-qPCR and in vitro co-culture experiments.Septic patients exhibited significantly reduced circulating ILC3 proportions.In mice,sepsis decreased colonic ILC3 numbers but enhanced IL-22 and GM-CSF production.ILC3 deficiency increased mortality and exacerbated intestinal barrier disruption,while exogenous IL-22/GM-CSF administration ameliorated colonic pathology.Mechanistically,sepsis induced metabolic reprogramming in ILC3,characteristiced by enhanced glycolysis,reduced mitochondrial mass and ATP producton,which led to mitochondrial ROS accumulation.ROS activated the NF-κB pathway to drive IL-22 and GM-CSF production.However,ROS scavening or NF-κB inhibition unexpectedly increased ILC3 apoptosis,revealing that ROS-NF-κB axis also conveys pro-survival signals.Despite enhanced function,the repair capacity of residual ILC3s was outpaced by ongoing intestinal destruction.Our finding provided insight into the relation of ROS-NF-κB axis with IL-22/GM-CSF production and the survival of remaining colonic ILC3s in sepsis.Thereby targeting this metabolic-immune crosstalk may present a therapeutic strategy to sepsis associated intestinal injury.
2026-09-02 | GSE322583 | GEO
Project description:The temporal evolution of sepsis was monitored by transcriptional profiling of five critically ill children with meningococcal sepsis and sepsis-induced multiple organ failure. Blood was sampled at 6 time points during the first 48 hours of their admission to pediatric intensive care, where the children received standard clinical treatment including organ support and antimicrobial therapy. Striking transcript instability was observed over the 48 hours, with increasing numbers of regulated genes over time. Most notably, proposed biomarkers for sepsis risk stratification also showed expression instability, with varied expression levels over 48 hours. This study demonstrates the extent of the complexity of temporal changes in gene expression that occur during the evolution of sepsis-induced multiple organ failure. Importantly, stratification tools that propose expression of biomarkers must take into account the temporal changes, over the use of single snapshots that may be less informative.
2013-04-03 | E-MEXP-3850 | biostudies-arrayexpress
Project description:Sepsis-associated cardiac dysfunction (SACD) is the predominant cause of death in sepsis patients with undefined mechanism of inflammation-autophagy interaction to date. Herein, time-course analysis of cardiac autophagy was conducted in a mouse model of SCAD. An in vitro model established by Lipopolysaccharide-induced macrophage conditioned media stimulation on cardiomyocytes was further investigated for molecular insights. We show cardiomyocyte Toll-like receptor 4 (cTLR4) serves as a central receptor mediating the crosstalk between cardiomyocyte and macrophage, and activation of cTLR4 intensifies the impairment of autophagic flux in cardiomyocytes. Mechanistically, the activation of cTLR4 inactivates TFEB, which largely depends on the E3 ligase activity of TRAF6. Moreover, computational simulation combined with experimental validation revealed the unique local electrostatic interactions between TRAF6 and TFEB. Collectively, our results highlight a previously undescribed role of cTLR4-TRAF6-TFEB signaling in modulating cardiac injury and identify the TRAF6-binding motif in TFEB as an attractive target for SACD therapy.
2021-10-15 | GSE185754 | GEO