In May 2023, a study led by Professor JunLing Liu from the School of Medicine, Shanghai Jiao Tong University, was published in the prestigious international academic journal ——Immunity (IF=43.474). The research, titled "STING activation in platelets aggravates septic thrombosis by enhancing platelet activation and granule secretion," delves into the molecular mechanisms of STING activation in platelets during the formation of septic thrombosis. The identified therapeutic target, C-ST5, holds the potential to alleviate excessive platelet activation and reduce thrombus formation. This study was also recently recognized as one of the "Top Ten Advances in Hematology in China in 2023."
Sepsis, a life-threatening condition marked by an overwhelming immune response to infection, often leads to severe complications, including septic thrombosis. Recent studies have uncovered the involvement of the STING (Stimulator of Interferon Genes) pathway in platelets during septic thrombosis, revealing complex molecular mechanisms that intertwine immunity and coagulation.
The study is meticulously designed to unravel the intricate mechanisms of STING activation in platelets during septic thrombosis. Adopting a multifaceted approach, researchers employ both in vitro and in vivo models to comprehensively investigate the molecular pathways influenced by STING activation.
In the in vitro experiments, platelets are subjected to cyclic GMP-AMP (cGAMP) to simulate STING activation. This controlled environment allows researchers to observe the precise changes in platelet behavior at the molecular level. Researchers delve into the changes in platelet morphology, granularity, and activation markers. The use of advanced imaging techniques allows for the visualization of granule-plasma membrane fusion and the subsequent release of platelet granules. By employing various techniques such as flow cytometry, immunofluorescence, and molecular assays, the study meticulously characterizes the impact of STING activation on platelet hyperactivation and granule secretion.
The in vivo component involves septic mouse models, where sepsis is induced to closely mimic the clinical conditions. This model enables researchers to assess the effects of STING activation on platelet function, thrombus formation, and overall survival. Through a combination of histopathological analyses, blood coagulation assays, and survival rate monitoring, the study gains insights into the systemic consequences of STING activation in a septic context.
The integration of these two models ensures a comprehensive understanding of the role of STING in platelets under both controlled and dynamic physiological conditions. This holistic study design is pivotal in capturing the nuances of STING-mediated platelet activation during septic thrombosis.
The results of the study provide a rich tapestry of insights into the role of STING activation in platelets during septic thrombosis. The in vitro experiments reveal a pronounced interaction between STING and syntaxin binding protein 2 (STXBP2), a key regulator of the SNARE complex assembly. This interaction is crucial for granule-plasma membrane fusion, and the study illustrates how cGAMP, the direct activator of STING, intensifies this process, leading to enhanced platelet hyperactivation.
The in vivo data corroborate these findings, demonstrating that C-ST5, a specific peptide inhibiting the binding of STING to STXBP2, effectively reduces thrombus formation in a septic mouse model. This promising result underscores the potential clinical applicability of STING-targeted interventions. The study not only unveils the intricacies of STING-mediated platelet activation but also provides a viable therapeutic strategy in C-ST5, offering hope for mitigating the complications of septic thrombosis.
In conclusion, the study provides a comprehensive understanding of STING activation in platelets during septic thrombosis, unraveling intricate molecular mechanisms. The identified therapeutic target, C-ST5, shows promise in mitigating platelet hyperactivation and reducing thrombus formation. This research not only contributes to our understanding of the pathophysiology of septic thrombosis but also opens avenues for the development of targeted therapies to improve patient outcomes in the challenging context of sepsis.
