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Updated: Jun 15, 2025
Use of Animal Model of Sepsis to Evaluate Novel Herbal Therapies
Published on: April 11, 2012
DOCK2 protects against bacterial sepsis by constraining T helper 1 response
Shusen Ye1,2, Linzi Huang1, Yuhao Zheng1
1Guangdong Provincial Key Laboratory of Immune Regulation and Immunotherapy, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China.
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.
Insights
Dedicator of cytokinesis 2 (DOCK2) protects against sepsis by limiting T helper 1 (Th1) cell responses. Targeting the DOCK2-Th1 axis offers a novel strategy for sepsis immunomodulatory therapy.
Area of Science:
- Immunology
- Molecular Biology
- Pathophysiology
Background:
- Sepsis is a life-threatening systemic response to infection, ranking among the top global causes of death.
- The molecular and cellular mechanisms underlying sepsis remain incompletely understood.
- Investigating novel regulatory factors is crucial for developing effective sepsis treatments.
Purpose of the Study:
- To elucidate the role of dedicator of cytokinesis 2 (DOCK2) in the host response to sepsis.
- To explore the impact of DOCK2 deficiency on inflammatory pathways and immune cell function during sepsis.
- To identify potential therapeutic targets within the DOCK2-mediated signaling network for sepsis management.
Main Methods:
- Established mouse models of sepsis using lipopolysaccharide (LPS) and *Escherichia coli* (*E. coli*) infection.
- Utilized flow cytometry and ELISA to quantify T helper 1 (Th1) cell subsets and serum pro-inflammatory cytokines.
- Conducted in vivo neutralization experiments targeting IFN-γ and CD4+ T cells, alongside RNA-sequencing (RNA-seq) analysis.
Main Results:
- DOCK2 acts as a critical downregulating factor in LPS signal pathways, with DOCK2-deficient mice exhibiting heightened sensitivity to sepsis.
- Increased levels of inflammatory cytokines, particularly IFN-γ, were observed in DOCK2-deficient mice, attributed to hyperresponsive Th1 cells.
- Neutralization of IFN-γ and CD4+ T cells ameliorated sepsis severity in DOCK2-deficient mice, confirming the protective role of DOCK2-mediated Th1 regulation.
Conclusions:
- DOCK2 plays a protective role in bacterial sepsis by constraining Th1 responses, thereby mitigating systemic inflammation and multi-organ injury.
- The DOCK2-Th1 axis represents a promising target for novel immunomodulatory therapies aimed at improving outcomes in sepsis.
- Targeting this axis could offer a new therapeutic strategy to manage systemic inflammatory responses associated with bacterial infections.
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