Exosomes from DGKK-Knockdown CD4+T Cells Alleviate Sepsis by Inhibiting the DAG/PKC/ROS Pathway-Mediated M1 Macrophage Polarization and Reducing Endothelial Permeability
4 affiliations
- 1Department of General Practice, Affiliated Hangzhou First People’s Hospital, Westlake University School of Medicine, Hangzhou, China
- 2Department of General Practice, Affiliated Zhejiang Commercial Bank Co., Ltd., Hangzhou, China
- 3The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
- 4Department of Emergency, Affiliated Hangzhou First People’s Hospital, School of Medicine, Westlake University, No. 261, Huansha Road, Shangcheng District, Hangzhou City, Zhejiang Province 310006 China
Abstract
Sepsis is a serious disease associated with macrophage polarization and endothelial permeability. The DAG/PKC/ROS pathway is crucial for sepsis development, macrophage polarization and endothelial permeability. As CD4+T cell-derived exosomes can modulate the DAG/PKC/ROS pathway, we aimed to investigate the role and mechanism of exosomes from DGKK-knockdown CD4+T cells in sepsis. RAW264.7 cells were exposed to lipopolysaccharide and interferon-gamma (L/I) to promote M1 polarization and then co-cultured with exosomes. The macrophages were co-cultured with lipopolysaccharide-stimulated PMVECs. Additionally, phorbol 12-myristate 13-acetate (PMA), a PKC agonist, was used to treat macrophages. Furthermore, sepsis mouse models were established via cecal ligation and puncture (CLP) surgery. In vitro, lipopolysaccharide increased DGKK expression in CD4⁺T cells and CD4⁺T cell-derived exosomes. L/I-induced M1 macrophage polarization and DAG/PKC/ROS pathway activation were amplified by lipopolysaccharide-stimulated CD4⁺T cell exosomes. However, exosomes from DGKK-knockdown CD4⁺T cells counteracted these effects. Furthermore, treatment with these exosomes improved PMVEC viability, decreased apoptosis, alleviated inflammation, and decreased permeability. In vivo, CLP-induced inflammation, organ (lung/liver/kidney) injury, M1 macrophage polarization, DAG/PKC/ROS pathway activation, and lung permeability were further aggravated by LPS-stimulated CD4⁺T cell exosomes. However, exosomes from DGKK-knockdown CD4⁺T cells counteracted these deteriorations, while macrophage depletion abolished the protective effects of DGKK-knockdown CD4⁺T cell-derived exosomes in sepsis. Importantly, the effects of exosomes from DGKK-knockdown CD4⁺T cells on M1 macrophage polarization and endothelial permeability were reversed by PMA. In conclusion, exosomes from DGKK-knockdown CD4+T cells mitigated sepsis by suppressing the DAG/PKC/ROS pathway-mediated M1 macrophage polarization and reducing endothelial permeability, suggesting DGKK as a promising therapeutic target for sepsis.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s10753-026-02566-8.
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BibTeX
@article{chen2026exosomes,
title = {{Exosomes from DGKK-Knockdown CD4+T Cells Alleviate Sepsis by Inhibiting the DAG/PKC/ROS Pathway-Mediated M1 Macrophage Polarization and Reducing Endothelial Permeability}},
author = {Wen Chen and Xiangye Bo and Qianqian Wang and Ye Zhou and Nuo Zhou and Jinhong Wu},
journal = {Inflammation},
year = {2026},
month = jul,
doi = {10.1007/s10753-026-02566-8},
url = {https://doi.org/10.1007/s10753-026-02566-8},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Exosomes from DGKK-Knockdown CD4+T Cells Alleviate Sepsis by Inhibiting the DAG/PKC/ROS Pathway-Mediated M1 Macrophage Polarization and Reducing Endothelial Permeability
AU - Wen Chen
AU - Xiangye Bo
AU - Qianqian Wang
AU - Ye Zhou
AU - Nuo Zhou
AU - Jinhong Wu
PY - 2026
DA - 2026/07/29
JO - Inflammation
DO - 10.1007/s10753-026-02566-8
UR - https://doi.org/10.1007/s10753-026-02566-8
AB - Sepsis is a serious disease associated with macrophage polarization and endothelial permeability. The DAG/PKC/ROS pathway is crucial for sepsis development, macrophage polarization and endothelial permeability. As CD4+T cell-derived exosomes can modulate the DAG/PKC/ROS pathway, we aimed to investigate the role and mechanism of exosomes from DGKK-knockdown CD4+T cells in sepsis. RAW264.7 cells were exposed to lipopolysaccharide and interferon-gamma (L/I) to promote M1 polarization and then co-cultured with exosomes. The macrophages were co-cultured with lipopolysaccharide-stimulated PMVECs. Additionally, phorbol 12-myristate 13-acetate (PMA), a PKC agonist, was used to treat macrophages. Furthermore, sepsis mouse models were established via cecal ligation and puncture (CLP) surgery. In vitro, lipopolysaccharide increased DGKK expression in CD4⁺T cells and CD4⁺T cell-derived exosomes. L/I-induced M1 macrophage polarization and DAG/PKC/ROS pathway activation were amplified by lipopolysaccharide-stimulated CD4⁺T cell exosomes. However, exosomes from DGKK-knockdown CD4⁺T cells counteracted these effects. Furthermore, treatment with these exosomes improved PMVEC viability, decreased apoptosis, alleviated inflammation, and decreased permeability. In vivo, CLP-induced inflammation, organ (lung/liver/kidney) injury, M1 macrophage polarization, DAG/PKC/ROS pathway activation, and lung permeability were further aggravated by LPS-stimulated CD4⁺T cell exosomes. However, exosomes from DGKK-knockdown CD4⁺T cells counteracted these deteriorations, while macrophage depletion abolished the protective effects of DGKK-knockdown CD4⁺T cell-derived exosomes in sepsis. Importantly, the effects of exosomes from DGKK-knockdown CD4⁺T cells on M1 macrophage polarization and endothelial permeability were reversed by PMA. In conclusion, exosomes from DGKK-knockdown CD4+T cells mitigated sepsis by suppressing the DAG/PKC/ROS pathway-mediated M1 macrophage polarization and reducing endothelial permeability, suggesting DGKK as a promising therapeutic target for sepsis. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s10753-026-02566-8.
SN - 0360-3997
SN - 1573-2576
ER -