2. Academic Validation
  3. Extracellular vesicles derived from CD4+ T cells carry DGKK to promote sepsis-induced lung injury by regulating oxidative stress and inflammation

Extracellular vesicles derived from CD4+ T cells carry DGKK to promote sepsis-induced lung injury by regulating oxidative stress and inflammation

  • Cell Mol Biol Lett. 2023 Mar 23;28(1):24. doi: 10.1186/s11658-023-00435-y.
Guo-Wei Tu # 1,  Yi Zhang # 2,  Jie-Fei Ma # 3,  Jun-Yi Hou 1,  Guang-Wei Hao 1,  Ying Su 1,  Jing-Chao Luo 1,  Lulu Sheng 4,  Zhe Luo 5 6 7 8
Affiliations

Affiliations

  • 1 Cardiac Intensive Care Center, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 2 Biomedical Research Center, Institute for Clinical Sciences, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 3 Department of Critical Care Medicine, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China.
  • 4 Department of Emergency Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China. yl20111211856@sjtu.edu.cn.
  • 5 Cardiac Intensive Care Center, Zhongshan Hospital, Fudan University, Shanghai, China. luo.zhe@zs-hospital.sh.cn.
  • 6 Department of Critical Care Medicine, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China. luo.zhe@zs-hospital.sh.cn.
  • 7 Shanghai Key Laboratory of Lung Inflammation and Injury, Shanghai, China. luo.zhe@zs-hospital.sh.cn.
  • 8 Department of Critical Care Medicine, Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, Fudan University, Shanghai, China. luo.zhe@zs-hospital.sh.cn.
  • # Contributed equally.
PMID: 36959535 DOI: 10.1186/s11658-023-00435-y
Abstract

Background: Sepsis is an abnormal immune response after Infection, wherein the lung is the most susceptible organ to fail, leading to acute lung injury. To overcome the limitations of current therapeutic strategies and develop more specific treatment, the inflammatory process, in which T cell-derived extracellular vesicles (EVs) play a central role, should be explored deeply.

Methods: Liquid chromatography-tandem mass spectrometry was performed for serum EV protein profiling. The serum diacylglycerol kinase kappa (DGKK) and endotoxin contents of patients with sepsis-induced lung injury were measured. Apoptosis, oxidative stress, and inflammation in A549 cells, bronchoalveolar lavage fluid, and lung tissues of mice were measured by flow cytometry, biochemical analysis, enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction, and western blot.

Results: DGKK, the key regulator of the diacylglycerol (DAG)/protein kinase C (PKC) pathway, exhibited elevated expression in serum EVs of patients with sepsis-induced lung injury and showed strong correlation with sepsis severity and disease progression. DGKK was expressed in CD4+ T cells under regulation of the NF-κB pathway and delivered by EVs to target cells, including alveolar epithelial cells. EVs produced by CD4+ T lymphocytes exerted toxic effects on A549 cells to induce apoptotic cell death, oxidative cell damage, and inflammation. In mice with sepsis induced by cecal ligation and puncture, EVs derived from CD4+ T cells also promoted tissue damage, oxidative stress, and inflammation in the lungs. These toxic effects of T cell-derived EVs were attenuated by the inhibition of PKC and NOX4, the downstream effectors of DGKK and DAG.

Conclusions: This approach established the mechanism that T-cell-derived EVs carrying DGKK triggered alveolar epithelial cell Apoptosis, oxidative stress, inflammation, and tissue damage in sepsis-induced lung injury through the DAG/PKC/NOX4 pathway. Thus, T-cell-derived EVs and the elevated distribution of DGKK should be further investigated to develop therapeutic strategies for sepsis-induced lung injury.

Keywords

DGKK; Extracellular vesicles; Inflammation; Oxidative stress; Sepsis-induced lung injury.

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