Frontiers in immunology · 2025
DOCK2 protects against bacterial sepsis by constraining T helper 1 response.
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Ye Shusen, Huang Linzi, Zheng Yuhao, Liu Shanshan, Wang Xiangyang, Yu Haoyuan, Zhu Lisi, Liang Texi, Wang Yifei, Zhang Chunmin, Wu Fan, Ye Lilin, Cao Yingjiao
Аннотация
BACKGROUND: Sepsis 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.
METHODS: A 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.
RESULTS: We 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.
CONCLUSION: Our 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.
METHODS: A 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.
RESULTS: We 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.
CONCLUSION: Our 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.