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Lactate inhibits T-cell activation in sepsis through CD40LG downregulation and SOCS3-mediated JAK1/STAT3 pathway
Hui Zhang1, Fanbing Meng1, Jinxuan Tang1
1Department of Anesthesiology and Perioperative Medicine, Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Clinical Research Center for Anesthesiology and Perioperative Medicine, Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China.
Objectives:
Lactate, an indicator of sepsis severity, affects kinase activity and is often associated with immunosuppression. This study investigates the impact of lactate on kinases and immune cells and identifies pivotal genes governing their interactions.
Methods:
Differentially expressed genes (DEGs) between sepsis and control groups were screened using the limma package. The correlation between lactate-related DEGs (lrDEGs) and kinase-related DEGs (krDEGs) was then assessed. Hub genes were identified using the algorithms in CytoHubba and weighted gene co-expression network analysis (WGCNA). The aberrant immune status of sepsis patients was evaluated using xCell. The findings were ultimately validated through cellular experiments.
Results:
In sepsis, a stronger correlation between lrDEGs and krDEGs was observed among the 998 identified DEGs compared to controls. Eight hub genes were identified through CytoHubba and WGCNA. The correlation between lrDEGs (or krDEGs) and T lymphoid cell score was particularly strong among the hub genes. CD40LG and SOCS3 were identified as key regulators of T cell function. These genes were closely associated with lrDEGs. Cellular experiments demonstrated that lactate inhibits T cell activation through downregulation of CD40LG and suppression of the SOCS3-mediated JAK1/STAT3 pathway.
Conclusion:
Lactate-induced inhibition of T lymphocyte activation in sepsis is associated with altered expression of kinase-related genes. Elevated lactate levels downregulate CD40LG and SOCS3 expression, leading to T cell suppression by inhibiting the JAK-STAT signaling pathway.
Insights
Elevated lactate levels in sepsis suppress T cell activation by downregulating CD40LG and SOCS3, impacting kinase activity and immune cell function. This study identifies key genes involved in lactate-induced immunosuppression.
Area of Science:
- Immunology
- Molecular Biology
- Biochemistry
Background:
- Lactate, a marker of sepsis severity, influences kinase activity and immune suppression.
- Understanding lactate's impact on immune cells and kinases is crucial for sepsis management.
Purpose of the Study:
- To investigate the effects of lactate on kinase activity and immune cells in sepsis.
- To identify key genes regulating the interactions between lactate, kinases, and immune cells.
Main Methods:
- Differential gene expression analysis (limma) to identify sepsis-related genes.
- Correlation analysis between lactate-related DEGs (lrDEGs) and kinase-related DEGs (krDEGs).
- Hub gene identification (CytoHubba, WGCNA) and immune cell profiling (xCell).
Main Results:
- A significant correlation between lrDEGs and krDEGs was observed in sepsis patients.
- Eight hub genes were identified, with strong associations between lrDEGs/krDEGs and T lymphoid cell scores.
- CD40LG and SOCS3 were identified as critical regulators of T cell function, linked to lrDEGs.
Conclusions:
- Lactate inhibits T lymphocyte activation in sepsis via altered kinase-related gene expression.
- Elevated lactate downregulates CD40LG and SOCS3, suppressing T cells by inhibiting the JAK-STAT pathway.
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