Integrative single-cell RNA sequencing and metabolomics decipher the imbalanced lipid-metabolism in maladaptive immune responses during sepsis

She, Han; Tan, Lei; Wang, Yi; Du, Yuanlin; Zhou, Yuanqun; Zhang, Jun; Du, Yong; Guo, Ningke; Wu, Zhengbin; Li, Qinghui; Bao, Daiqin; Mao, Qingxiang; Hu, Yi; Liu, Liangming; Li, Tao

doi:10.3389/fimmu.2023.1181697

Cited by 11 publications

(3 citation statements)

References 45 publications

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“…The single-sample Gene Set Enrichment Analysis (ssGSEA) method was used to assess the level of immune cell infiltration in sepsis samples across different MAAGs subgroups, utilizing the "GSVA" R package 10 . ssGSEA requires predefined gene sets that are indicative of specific immune cell types.…”

Section: Methodsmentioning

confidence: 99%

Development of macrophage-associated genes prognostic signature predicts clinical outcome and immune infiltration for sepsis

Ma,

Wu,

et al. 2024

Sci Rep

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Sepsis is a major global health problem, causing a significant burden of disease and death worldwide. Risk stratification of sepsis patients, identification of severe patients and timely initiation of treatment can effectively improve the prognosis of sepsis patients. We procured gene expression datasets for sepsis (GSE54514, GSE65682, GSE95233) from the Gene Expression Omnibus and performed normalization to mitigate batch effects. Subsequently, we applied weighted gene co-expression network analysis to categorize genes into modules that exhibit correlation with macrophage activity. To pinpoint macrophage-associated genes (MAAGs), we executed differential expression analysis and single sample gene set enrichment analysis. We then established a prognostic model derived from four MAAGs that were significantly differentially expressed. Functional enrichment analysis and immune infiltration assessments were instrumental in deciphering the biological mechanisms involved. Furthermore, we employed principal component analysis and conducted survival outcome analyses to delineate molecular subgroups within sepsis. Four novel MAAGs—CD160, CX3CR1, DENND2D, and FAM43A—were validated and used to create a prognostic model. Subgroup classification revealed distinct molecular profiles and a correlation with 28-day survival outcomes. The MAAGs risk score was developed through univariate Cox, LASSO, and multivariate Cox analyses to predict patient prognosis. Validation of the risk score upheld its prognostic significance. Functional enrichment implicated ribonucleoprotein complex biogenesis, mitochondrial matrix, and transcription coregulator activity in sepsis, with an immune infiltration analysis indicating an association between MAAGs risk score and immune cell populations. The four MAAGs exhibited strong diagnostic capabilities for sepsis. The research successfully developed a MAAG-based prognostic model for sepsis, demonstrating that such genes can significantly stratify risk and reflect immune status. Although in-depth mechanistic studies are needed, these findings propose novel targets for therapy and provide a foundation for future precise clinical sepsis management.

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Section: Methodsmentioning

confidence: 99%

Development of macrophage-associated genes prognostic signature predicts clinical outcome and immune infiltration for sepsis

Ma,

Wu,

et al. 2024

Sci Rep

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“…Lipids are an essential part of a cell’s biomolecular pool and play important roles in a myriad of complex biological processes with biophysical, energy storage, and signaling functions (reviewed in − ). Recent studies demonstrate that analyzing lipids at the single-cell level not only reveals significant variation in lipid profiles between different cells − but is also capable of observing putative response to stimuli, such as treatment with drugs or exogenous fatty acids. − Cancer cells are highly heterogeneous and very diverse in their phenotype which makes them hard to extinguish, but the analysis of single cells and the characterization of the heterogeneity could provide new treatment strategies . Pancreatic ductal adenocarcinoma is the most common pancreatic cancer with the poorest prognosis for pancreatic diseases .…”

Section: Introductionmentioning

confidence: 99%

Single-Cell Untargeted Lipidomics Using Liquid Chromatography and Data-Dependent Acquisition after Live Cell Selection

von Gerichten,

Saunders,

Kontiza

et al. 2024

Anal. Chem.

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We report the development and validation of an untargeted single-cell lipidomics method based on microflow chromatography coupled to a data-dependent mass spectrometry method for fragmentation-based identification of lipids. Given the absence of single-cell lipid standards, we show how the methodology should be optimized and validated using a dilute cell extract. The methodology is applied to dilute pancreatic cancer and macrophage cell extracts and standards to demonstrate the sensitivity requirements for confident assignment of lipids and classification of the cell type at the single-cell level. The method is then coupled to a system that can provide automated sampling of live, single cells into capillaries under microscope observation. This workflow retains the spatial information and morphology of cells during sampling and highlights the heterogeneity in lipid profiles observed at the single-cell level. The workflow is applied to show changes in single-cell lipid profiles as a response to oxidative stress, coinciding with expanded lipid droplets. This demonstrates that the workflow is sufficiently sensitive to observing changes in lipid profiles in response to a biological stimulus. Understanding how lipids vary in single cells will inform future research into a multitude of biological processes as lipids play important roles in structural, biophysical, energy storage, and signaling functions.

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“… 3 The heart was the organ most commonly implicated in hemorrhagic shock, and once cardiac dysfunction happened, the prognosis further deteriorated. 4 , 5 Previous studies reported that the mechanisms of myocardial injury in hemorrhagic shock were mainly related to inflammation, autonomic dysfunction, and apoptosis. 6 , 7 However, the therapeutic efficacy targeted to these mechanisms was not ideal.…”

Section: Introductionmentioning

confidence: 99%

The New Nano-Resuscitation Solution (TPP-MR) Attenuated Myocardial Injury in Hemorrhagic Shock Rats by Inhibiting Ferroptosis

Tan,

She,

Wang

et al. 2024

IJN

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Background Hemorrhagic shock was a leading cause of death worldwide, with myocardial injury being a primary affected organ. As commonly used solutions in fluid resuscitation, acetated Ringer’s (AR) and Lactate Ringer’s solution (LR) were far from perfect for their adverse reactions such as lactic acidosis and electrolyte imbalances. In previous studies, TPP@PAMAM-MR (TPP-MR), a novel nanocrystal resuscitation fluid has been found to protect against myocardial injury in septic rats. However, its role in myocardial injury in rats with hemorrhagic shock and underlying mechanism is unclear. Methods The hemorrhagic shock rats and hypoxia-treated cardiomyocytes (H9C2) were utilized to investigate the impact of TPP-MR on cardiac function, mitochondrial function, and lipid peroxidation. The expressions of ferritin-related proteins glutathione peroxidase 4 (GPX4), Acyl CoA Synthase Long Chain Family Member 4 (ACSL4), and Cyclooxygenase-2(COX2) were analyzed through Western blotting to explore the mechanism of TPP-MR on hemorrhagic myocardial injury. Results TPP-MR, a novel nanocrystalline resuscitation fluid, was synthesized using TPP@PAMAM@MA as a substitute for L-malic acid. We found that TPP-MR resuscitation significantly reduced myocardial injury reflected by enhancing cardiac output, elevating mean arterial pressure (MAP), and improving perfusion. Moreover, TPP-MR substantially prolonged hemorrhagic shock rats’ survival time and survival rate. Further investigations indicated that TPP-MR improved the mitochondrial function of myocardial cells, mitigated the production of oxidative stress agents (ROS) and increased the glutathione (GSH) content. Additionally, TPP-MR inhibited the expression of the ferroptosis-associated GPX4 protein, ACSL4 and COX2, thereby enhancing the antioxidant capacity. Conclusion The results showed that TPP-MR had a protective effect on myocardial injury in rats with hemorrhagic shock, and its mechanism might be related to improving the mitochondrial function of myocardial cells and inhibiting the process of ferroptosis.

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Integrative single-cell RNA sequencing and metabolomics decipher the imbalanced lipid-metabolism in maladaptive immune responses during sepsis

Cited by 11 publications

References 45 publications

Development of macrophage-associated genes prognostic signature predicts clinical outcome and immune infiltration for sepsis

Development of macrophage-associated genes prognostic signature predicts clinical outcome and immune infiltration for sepsis

Single-Cell Untargeted Lipidomics Using Liquid Chromatography and Data-Dependent Acquisition after Live Cell Selection

The New Nano-Resuscitation Solution (TPP-MR) Attenuated Myocardial Injury in Hemorrhagic Shock Rats by Inhibiting Ferroptosis

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