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
Guangdong Provincial Key Laboratory of Immune Regulation and Immunotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China.
Institute of Immunological Innovation and Translation, Institute of Life Sciences, Chongqing Medical University, Chongqing, China.
Front Immunol. 2025 May 29;16:1527934. doi: 10.3389/fimmu.2025.1527934. eCollection 2025.
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.
A mouse sepsis model was established through LPS induction and () 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.
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 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 mice. Mechanically, DOCK2-mediated cell cycle progression and cytokine signaling act in concert to govern peripheral Th1 cell fate.
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.
脓毒症是机体对感染的一种全身性反应，可导致危及生命的后果，在全球十大死因中名列前茅。然而，我们对脓毒症分子和细胞影响的理解仍然很基础。
通过脂多糖（LPS）诱导和（）感染建立小鼠脓毒症模型。采用流式细胞术和酶联免疫吸附测定（ELISA）检测脓毒症小鼠中的辅助性T细胞1（Th1）亚群和血清促炎细胞因子。此外，进行体内中和实验分别阻断干扰素-γ（IFN-γ）和CD4+T细胞，以探讨DOCK2对脓毒症小鼠的调节作用。最后，使用体内RNA测序系统分析DOCK2的调节机制。
我们确定胞质分裂 dedicator 2（DOCK2）是LPS信号通路的关键下调因子。DOCK2基因缺陷小鼠对LPS诱导的脓毒症和脓毒症高度敏感，炎症细胞因子水平升高，尤其是IFN-γ，这主要归因于反应过度的Th1细胞。此外，我们通过中和IFN-γ和CD4验证了DOCK2介导的Th1细胞在脓毒症中的重要作用，发现两者的阻断均降低了小鼠脓毒症的严重程度。从机制上讲，DOCK2介导的细胞周期进程和细胞因子信号传导共同作用以控制外周Th1细胞命运。
我们的数据表明，DOCK2通过抑制Th1反应在调节细菌性脓毒症中的全身炎症和多器官损伤方面发挥保护作用。这些发现为脓毒症的免疫调节治疗提供了新靶点，表明靶向DOCK2-Th1轴可能成为改善与细菌感染相关的全身炎症反应的新策略。
