Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Pharmacological elevation of lactate alleviates sepsis via histone lactylation-induced IL-10 production

ABSTRACT: Despite that lactate accumulation is deemed to be a marker of severe sepsis, lactate-driven histone lactylation induces transcription of homeostatic genes. Thus, the biological roles of lactate in sepsis remain unknown. Here, we report that amlexanox, an anti-inflammatory drug, improves survival, mitigates multiorgan dysfunction, and suppresses inflammatory infiltrates in endotoxemia and sepsis. Mechanistically, amlexanox elevates intracellular lactate to enhance histone lactylation of IL10 gene promoter and IL-10 production to alleviate sepsis. Blocking IL-10 receptor nearly abrogates therapeutic effect of amlexanox, and inhibiting lactate production abrogates amlexanox-induced IL-10. Amlexanox treatment significantly downregulates gene expression of electron transport chain, indicating it elevates lactate level by breaking aerobic respiration. Importantly, in vivo sodium lactate administration improves survival in endotoxemia. Our study clarifies that elevating lactate-mediated histone lactylation plays a protective role in sepsis, and amlexanox is a potential drug for sepsis.

ORGANISM(S): Mus musculus

PROVIDER: GSE318448 | GEO | 2026/02/07

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Pharmacological elevation of lactate alleviates sepsis via histone lactylation-induced IL-10 production

Project description:Pharmacological elevation of lactate alleviates sepsis via histone lactylation-induced IL-10 production

| PRJNA1418745 | ENA

Histone lactylation drives endothelial activation-mediated lung injury in sepsis-associated ARDS via promoting ferroptosis

Project description:The activation of pulmonary endothelial cells (ECs) triggers the occurrence of lung injury and is a hallmark of sepsis-associated acute respiratory distress syndrome(ARDS). Aberrant metabolism favoring glycolysis plays a pivotal role in the pathogenesis of sepsis-induced EC activation. Herein we demonstrate that glycolysis-related histone lactylation, represented by H3K14 lactylation (H3K14la), drives sepsis-associated EC activation and lung injury. Accordingly, H3K14la level is elevated in injured lung tissue and activated ECs. Inhibition of lactate production suppresses both H3K14la levels and EC activation in response to lipopolysaccharide (LPS). We also show that lactate-dependent H3K14la is enriched at the promoters of ferroptosis-related genes, thereby inducing ferroptosis in ECs, and inhibiting ferroptosis effectively ameliorates EC activation. Taken together, elevated lactate in sepsis modulates EC activation and lung injury via histone lactylation and manipulation of glycolysis/H3K14la/ferroptosis axis may provide novel therapeutic approaches for the treatment of sepsis-associated ARDS.

2023-01-01 | GSE212087 | GEO

Effects of ENO1 knockdown and LPS+Lactate stimulation on EA.HY926 cells

Project description:Elevated lactate was associated with vascular endothelial cells (ECs) dysfunction in sepsis. However, the underlying mechanisms remain to be defined. In this study, we found that elevated lactate in sepsis promotes lactylation of enolase 1 (ENO1) at K71 site through the action of lactyltransferase P300. The lactylation at ENO1 K71 site reduces the binding of TRIM21(an E3 ubiquitin ligase) mRNA to ENO1 (an RNA-binding protein), resulting in enhanced TRIM21 mRNA stability and expression. Elevated TRIM21 can bind to VE-Cadherin and exert its E3 ubiquitin ligase function, causing the ubiquitination and degradation of VE-Cadherin, which disrupts endothelial adhesions junctions (AJs) and increases endothelial permeability. Targeting lactylation of ENO1 K71 via a specific peptide alleviated endothelial injury and enhanced survival rates among septic mice. These findings suggest that lactyaltion of ENO1 plays a pivotal role in vascular endothelial dysfuncyion during sepsis, while inhibiting lactylation may offer a novel strategy for sepsis treatment.

2026-01-21 | GSE281679 | GEO

H3K14la drives endothelial dysfunction in sepsis-induced ARDS via promoting SLC40A1/TFR-mediated ferroptosis

Project description:Background: Pulmonary endothelial cell (EC) activation is a key factor in acute respiratory distress syndrome (ARDS). In sepsis, increased glycolysis leads to lactate buildup, which induces lysine lactylation (Kla) on histones and other proteins. However, the role of protein lactylation in EC dysfunction during sepsis-induced ARDS remains unclear. Methods: Integrative lactylome and proteome analysis was performed to identify the global lactylome profiling in lung tissues of septic mice. Cut&Tag analysis were used to identify the transcriptional targets of histone H3 lysine 14 lactylation (H3K14la) in ECs. Results: Septic mice exhibited elevated levels of lactate and H3K14la in lung tissues, particularly in pulmonary ECs. Suppressing glycolysis reduced both H3K14la and EC activation, suggesting a link between glycolysis and lactylation. Moreover, H3K14la was found to be enriched at promoter regions of ferroptosis-related genes such as transferrin receptor (TFRC) and solute carrier family 40 member 1 (SLC40A1), which contributed to EC activation and lung injury under septic conditions. Conclusions: We for the first time reported the role of lactate-dependent H3K14 lactylation in regulating EC ferroptosis to promote vascular dysfunction during sepsis-induced lung injury. Our findings suggest that manipulation of glycolysis/H3K14la/ferroptosis axis may provide novel therapeutic approaches for sepsis-associated ARDS.

2025-05-07 | PXD056805 | Pride

Lactate-mediated histone lactylation promotes melanoma angiogenesis

Project description:The pathogenesis of cancer is rather complicated and includes multiple aspects, with metabolic reprogramming and angiogenesis as the leading hallmark characteristics. Recent reports have unveiled that the glycolytic metabolite lactate could modify histone lactylation level to epigenetically regulate gene expressions and biological processes in cancer, while the role of lactate-mediated histone lactylation in tumor angiogenesis remains elusive. By taking advantage of melanoma as the model, we demonstrate that lactate-mediated histone lactylation promotes tumor angiogenesis via IL-33/ST2 axis.

2025-12-02 | GSE289136 | GEO

Histone lactylation mediated by Fam172a in POMC neurons regulates energy balance [CUT&TAG]

Project description:Glycolysis-derived lactate was identified as substrate for histone lactylation, which has been regarded as a significant role in transcriptional regulation in many tissues. However, the role of histone lactylation in the metabolic center, the hypothalamus, is still unknown. Here, we show that hypothalamic pro-opiomelanocortin (POMC) neuron-specific deletion of family with sequence similarity 172, member A (Fam172a) can increase histone lactylation and protect mice against diet-induced obesity (DIO) and related metabolic disorders. Conversely, overexpression of Fam172a in POMC neurons led to an obesity-like phenotype. Using RNA-seq and CUT&Tag chromatin profiling analyses, we find that knockdown of Fam172a activates the glycolytic process and increases peptidylglycine α-amidating monooxygenase (PAM), which affects the synthesis of α-MSH, via H4K12la (histone lactylation). In addition, pharmacological inhibition of lactate production clearly abrogates the anti-obesity effect of PFKO (POMC-Cre, Fam172aloxP/loxP, POMC neurons Fam172a knockout). These findings highlight the importance of Fam172a and lactate in the development of obesity.

2024-11-06 | GSE280695 | GEO

Histone lactylation mediated by Fam172a in POMC neurons regulates energy balance [RNA-seq]

2024-11-06 | GSE280694 | GEO

ChIP-seq of H3K18la in murine Th17-differentiated T cells

Project description:Increased lactate levels in the tissue microenvironment are a well-known feature of chronic inflammation. However, the role of lactate in regulating T cell function remains controversial. We here demonstrate that extracellular lactate predominantly induces deregulation of the Th17-specific gene expression program by modulating metabolic and epigenetic status of Th17 cells. Following lactate treatment, Th17 cells significantly reduced their IL-17A production and upregulated Foxp3 expression through ROS-driven IL-2 secretion. Moreover, we observed a broad pattern of histone lactylation at various genes in CD4+ T cells, with particularly highly enriched lactylation of histone H3 at the Foxp3 promoter regions in lactate-treated Th17 cells. These results indicate that lactate is capable of reprogramming pro-inflammatory T cell phenotype into regulatory T cells. Moreover, we show that high lactate concentrations suppress the Th17 pathogenicity during intestinal inflammation. Collectively, these findings have a potential therapeutic value for development of novel clinical strategies to target inflammatory and autoimmune diseases.

2022-11-25 | GSE208727 | GEO

Neutrophil KLF2 regulates inflammasome-dependent neonatal mortality from endotoxemia

Project description:Preterm neonates die at a significantly higher rate from sepsis than full-term neonates, attributable to their dysregulated immune response. In addition to tissue destruction caused directly by bacterial invasion, an overwhelming cytokine response by the immune cells to bacterial antigens also results in collateral damage. Sepsis leads to decreased gene expression of a critical transcription factor, Kruppel-like factor-2 (KLF2), a tonic repressor of myeloid cell activation. KLF2 gene expression is also lower in murine pups at an earlier postnatal age. Using a murine model of myeloid-KLF2 deletion, we show that loss of KLF2 leads to decreased survival after endotoxemia in a developmentally dependent manner, with increased mortality at postnatal day 4 (P4) compared to P12 pups. This survival is significantly increased by neutrophil depletion before endotoxemia. P4 knockout pups have increased pro-inflammatory cytokine levels after endotoxemia compared to P4 controls or P12 pups, with significantly increased levels of IL-1b, an end product of the activation of the NLRP3 inflammasome complex. Both loss of myeloid KLF2 and a younger postnatal age lead to increased NLRP3 protein expression and release of IL-1b in bone marrow neutrophils. Inhibition of NLRP3 inflammasome activation by MCC950 significantly increased survival after endotoxemia in P4 pups. Transcriptomic analysis of bone marrow neutrophils showed that loss of myeloid-KLF2 is associated with gene enrichment of pro-inflammatory pathways in a developmentally dependent manner. These data suggest that targeting KLF2 could be a novel strategy to decrease the pro-inflammatory cytokine storm in neonatal sepsis and improve survival in neonates with sepsis.

2025-03-10 | GSE278604 | GEO

Histone lactylation during host–pathogen interaction: An intimate and persistent affair between Pseudomonas aeruginosa quorum-sensing signaling and host lactate [CUT&RUN]

Project description:Bacteria can stimulate host lactate production, aiding their colonization and virulence. However, the role of pathogen-driven host lactate remains underexplored. We show that Pseudomonas aeruginosa (PA)-secreted quorum-sensing (QS) signaling molecule 2’-aminoacetophenone (2-AA) elevates and sustains lactate in PA-infected immune-cells and animal tissues. In support, 2-AA increases the protein abundance of the lactate transporter, MCT4, and lactyl-coenzyme A synthetase (guanosine triphosphate (GTP)-specific SCS (GTPSCS)), and GTPSCS’s interaction with the transcriptional coactivators CREB-binding protein (CBP) and p300. Lactate augmentation drives histone H3 lysine 18 lactylation (H3K18la) enrichment at the regulatory regions of key immune and metabolic genes. H3K18la and consequent transcriptional changes promote PA survival in macrophages. Inhibition of lactate or 2-AA synthesis impedes lactate augmentation and H3K18la and reduces PA survival in macrophages. The uncovered QS-driven H3K18la represents a seminal interplay during host-pathogen interaction. Targeting this QS-epigenetic axis may offer a viable therapeutic approach for chronic PA infection.

2025-12-01 | GSE302326 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data