Lactate inhibits T-cell activation in sepsis through CD40LG downregulation and SOCS3-mediated JAK1/STAT3 pathway suppression

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease Pub Date : 2025-05-26 DOI:10.1016/j.bbadis.2025.167923

Hui Zhang , Fanbing Meng , Jinxuan Tang , Meixian Zhang , Qi Jing , Guotao Peng , Xiaoxiao Sun , Cheng Li

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引用次数: 0

Abstract

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.

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乳酸通过下调CD40LG和socs3介导的JAK1/STAT3通路抑制败血症中的t细胞活化

乳酸是脓毒症严重程度的一个指标，它影响激酶活性，通常与免疫抑制有关。本研究调查了乳酸对激酶和免疫细胞的影响，并确定了控制它们相互作用的关键基因。方法采用limma包筛选脓毒症组与对照组的差异表达基因（DEGs）。然后评估乳酸相关DEGs （lrDEGs）和激酶相关DEGs （krDEGs）之间的相关性。利用CytoHubba和加权基因共表达网络分析（weighted gene co-expression network analysis， WGCNA）中的算法鉴定Hub基因。应用xCell评估脓毒症患者的异常免疫状态。这些发现最终通过细胞实验得到了验证。结果在脓毒症中，与对照组相比，998个鉴定的DEGs中lrDEGs和krDEGs的相关性更强。通过CytoHubba和WGCNA鉴定出8个枢纽基因。lrDEGs（或krDEGs）与T淋巴样细胞评分之间的相关性在枢纽基因中尤为明显。CD40LG和SOCS3被确定为T细胞功能的关键调节因子。这些基因与lrdeg密切相关。细胞实验表明，乳酸通过下调CD40LG和抑制socs3介导的JAK1/STAT3通路抑制T细胞活化。结论乳酸对脓毒症患者T淋巴细胞活化的抑制作用与激酶相关基因的表达改变有关。乳酸水平升高下调CD40LG和SOCS3的表达，通过抑制JAK-STAT信号通路导致T细胞抑制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biochimica et biophysica acta. Molecular basis of disease 生物-生化与分子生物学

CiteScore

12.30

自引率

0.00%

发文量

218

审稿时长

32 days

期刊介绍： BBA Molecular Basis of Disease addresses the biochemistry and molecular genetics of disease processes and models of human disease. This journal covers aspects of aging, cancer, metabolic-, neurological-, and immunological-based disease. Manuscripts focused on using animal models to elucidate biochemical and mechanistic insight in each of these conditions, are particularly encouraged. Manuscripts should emphasize the underlying mechanisms of disease pathways and provide novel contributions to the understanding and/or treatment of these disorders. Highly descriptive and method development submissions may be declined without full review. The submission of uninvited reviews to BBA - Molecular Basis of Disease is strongly discouraged, and any such uninvited review should be accompanied by a coverletter outlining the compelling reasons why the review should be considered.