DOCK2 protects against bacterial sepsis by constraining T helper 1 response
BackgroundSepsis is a systemic host response to infection with life-threatening consequence which ranks among the top ten causes of death worldwide. Nevertheless, our understanding of the molecular and cellular impact of sepsis remains rudimentary.MethodsA mouse sepsis model was established through...
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Frontiers Media S.A.
2025-05-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1527934/full |
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| author | Shusen Ye Shusen Ye Linzi Huang Yuhao Zheng Shanshan Liu Xiangyang Wang Haoyuan Yu Haoyuan Yu Lisi Zhu Texi Liang Yifei Wang Chunmin Zhang Fan Wu Lilin Ye Lilin Ye Yingjiao Cao Yingjiao Cao |
| author_facet | Shusen Ye Shusen Ye Linzi Huang Yuhao Zheng Shanshan Liu Xiangyang Wang Haoyuan Yu Haoyuan Yu Lisi Zhu Texi Liang Yifei Wang Chunmin Zhang Fan Wu Lilin Ye Lilin Ye Yingjiao Cao Yingjiao Cao |
| author_sort | Shusen Ye |
| collection | DOAJ |
| description | BackgroundSepsis is a systemic host response to infection with life-threatening consequence which ranks among the top ten causes of death worldwide. Nevertheless, our understanding of the molecular and cellular impact of sepsis remains rudimentary.MethodsA mouse sepsis model was established through LPS induction and Escherichia coli (E. coli) infection. Flow cytometry and enzyme-linked immunosorbent assay (ELISA) were used to detect T helper 1 (Th1) cell subsets and serum pro-inflammatory cytokines in septic mice. Additionally, in vivo neutralization experiments were conducted to block IFN-γ and CD4+ T cells, respectively, to explore the regulatory effect of DOCK2 on septic mice. Finally, the regulatory mechanism of DOCK2 was analyzed using an in vivo RNA-seq system.ResultsWe identified dedicator of cytokinesis 2 (DOCK2) is a critical downregulating factor for LPS signal pathways. DOCK2-deficient mice were highly sensitive to LPS-induced sepsis and E. coli sepsis with increased levels of inflammatory cytokines, especially IFN-γ which were mainly due to hyperresponsive Th1 cells. Ulteriorly, we verified the vital role of DOCK2-mediated Th1 cells in sepsis by neutralizing both IFN-γ and CD4 and found both of which blockade reduced the severity of sepsis in Dock2−/− mice. Mechanically, DOCK2-mediated cell cycle progression and cytokine signaling act in concert to govern peripheral Th1 cell fate.ConclusionOur data indicates that DOCK2 acts as a protective role in regulating systemic inflammation and multi-organ injury in bacterial sepsis by constraining Th1 response. These findings provide new targets for immunomodulatory therapy of sepsis, suggesting that targeting the DOCK2-Th1 axis may become a new strategy to improve systemic inflammatory responses associated with bacterial infections. |
| format | Article |
| id | doaj-art-908b92da75564740b0acf4a5d79ac84c |
| institution | DOAJ |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-908b92da75564740b0acf4a5d79ac84c2025-08-20T03:05:46ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-05-011610.3389/fimmu.2025.15279341527934DOCK2 protects against bacterial sepsis by constraining T helper 1 responseShusen Ye0Shusen Ye1Linzi Huang2Yuhao Zheng3Shanshan Liu4Xiangyang Wang5Haoyuan Yu6Haoyuan Yu7Lisi Zhu8Texi Liang9Yifei Wang10Chunmin Zhang11Fan Wu12Lilin Ye13Lilin Ye14Yingjiao Cao15Yingjiao Cao16Guangdong Provincial Key Laboratory of Immune Regulation and Immunotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, ChinaInstitute of Immunological Innovation and Translation, Institute of Life Sciences, Chongqing Medical University, Chongqing, ChinaGuangdong Provincial Key Laboratory of Immune Regulation and Immunotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Immune Regulation and Immunotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Immune Regulation and Immunotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, ChinaGuangdong Cardiovascular Institute, Guangdong, Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, ChinaDepartment of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Immune Regulation and Immunotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Immune Regulation and Immunotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, ChinaInstitute of Immunological Innovation and Translation, Institute of Life Sciences, Chongqing Medical University, Chongqing, ChinaPediatric Intensive Care Unit, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, ChinaDepartment of Neonatology, Guangzhou Key Laboratory of Neonatal Intestinal Diseases, the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Immune Regulation and Immunotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, ChinaInstitute of Immunology, Third Military Medical University, Chongqing, ChinaGuangdong Provincial Key Laboratory of Immune Regulation and Immunotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, ChinaDepartment of Immunology and Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, ChinaBackgroundSepsis is a systemic host response to infection with life-threatening consequence which ranks among the top ten causes of death worldwide. Nevertheless, our understanding of the molecular and cellular impact of sepsis remains rudimentary.MethodsA mouse sepsis model was established through LPS induction and Escherichia coli (E. coli) infection. Flow cytometry and enzyme-linked immunosorbent assay (ELISA) were used to detect T helper 1 (Th1) cell subsets and serum pro-inflammatory cytokines in septic mice. Additionally, in vivo neutralization experiments were conducted to block IFN-γ and CD4+ T cells, respectively, to explore the regulatory effect of DOCK2 on septic mice. Finally, the regulatory mechanism of DOCK2 was analyzed using an in vivo RNA-seq system.ResultsWe identified dedicator of cytokinesis 2 (DOCK2) is a critical downregulating factor for LPS signal pathways. DOCK2-deficient mice were highly sensitive to LPS-induced sepsis and E. coli sepsis with increased levels of inflammatory cytokines, especially IFN-γ which were mainly due to hyperresponsive Th1 cells. Ulteriorly, we verified the vital role of DOCK2-mediated Th1 cells in sepsis by neutralizing both IFN-γ and CD4 and found both of which blockade reduced the severity of sepsis in Dock2−/− mice. Mechanically, DOCK2-mediated cell cycle progression and cytokine signaling act in concert to govern peripheral Th1 cell fate.ConclusionOur data indicates that DOCK2 acts as a protective role in regulating systemic inflammation and multi-organ injury in bacterial sepsis by constraining Th1 response. These findings provide new targets for immunomodulatory therapy of sepsis, suggesting that targeting the DOCK2-Th1 axis may become a new strategy to improve systemic inflammatory responses associated with bacterial infections.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1527934/fullDOCK2Th1LPSsepsisE.coli |
| spellingShingle | Shusen Ye Shusen Ye Linzi Huang Yuhao Zheng Shanshan Liu Xiangyang Wang Haoyuan Yu Haoyuan Yu Lisi Zhu Texi Liang Yifei Wang Chunmin Zhang Fan Wu Lilin Ye Lilin Ye Yingjiao Cao Yingjiao Cao DOCK2 protects against bacterial sepsis by constraining T helper 1 response Frontiers in Immunology DOCK2 Th1 LPS sepsis E.coli |
| title | DOCK2 protects against bacterial sepsis by constraining T helper 1 response |
| title_full | DOCK2 protects against bacterial sepsis by constraining T helper 1 response |
| title_fullStr | DOCK2 protects against bacterial sepsis by constraining T helper 1 response |
| title_full_unstemmed | DOCK2 protects against bacterial sepsis by constraining T helper 1 response |
| title_short | DOCK2 protects against bacterial sepsis by constraining T helper 1 response |
| title_sort | dock2 protects against bacterial sepsis by constraining t helper 1 response |
| topic | DOCK2 Th1 LPS sepsis E.coli |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1527934/full |
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