Article Impact Level: HIGH Data Quality: STRONG Summary of Nature Communications, 15(1), 7023. https://doi.org/10.1038/s41467-024-51211-1 Dr. Sara Baratchi et al.
Points
- The study investigates how shear stress influences neutrophil extracellular trap (NET) formation, linked to sterile inflammation and thrombosis.
- Controlled shear stress levels were applied to human neutrophils in microfluidic environments, revealing that increased shear stress significantly enhances NET formation.
- The mechanosensitive ion channel Piezo1 was identified as a critical mediator, triggering intracellular calcium influx, calpain activation, and cytoskeletal changes necessary for NETosis.
- Activation of Piezo1 not only induces NETosis but also heightens neutrophil sensitivity to pro-inflammatory stimuli like ATP and LPS.
- Targeting the Piezo1 pathway could offer therapeutic potential for managing diseases related to excessive NET formation, such as autoimmune diseases, sepsis, and thrombosis.
Summary
This study delves into the mechanistic study of neutrophil extracellular trap formation (NETosis) under shear stress, revealing critical insights into the cellular processes contributing to sterile inflammation and thrombosis. The study employed advanced methodologies to expose human neutrophils to controlled levels of shear stress in microfluidic environments, measuring changes in cellular morphology, activation markers, and NET formation. It was observed that exposure to increasing shear stress levels significantly upregulated the formation of NETs, which are structures composed of expelled DNA and antimicrobial proteins that trap pathogens but also have a role in clotting and inflammation when dysregulated.
Key findings from the study highlighted the pivotal role of the mechanosensitive ion channel Piezo1 in mediating the effects of shear stress on neutrophils. Activation of Piezo1 led to increased intracellular calcium levels, triggering a cascade of events, including calpain activation and cytoskeletal remodeling, which are essential for NETosis. The research demonstrated that the activation of Piezo1 under shear stress conditions not only induced NETosis but also enhanced the neutrophils’ responsiveness to other pro-inflammatory stimuli like adenosine triphosphate (ATP) and lipopolysaccharides (LPS), commonly associated with infections.
The clinical implications of these findings are significant, especially in understanding how hemodynamic forces in blood vessels could influence neutrophil behavior and contribute to inflammatory diseases and thrombotic events. The study suggests that targeting the Piezo1 pathway might offer therapeutic potential in managing diseases characterized by unwanted NET formation and related complications. Further research could explore the modulation of Piezo1 activity to mitigate the adverse effects of exaggerated NETosis in clinical settings, offering new strategies to treat or prevent conditions like autoimmune diseases, sepsis, and thrombosis where sterile inflammation plays a critical role.
Link to the article: https://www.nature.com/articles/s41467-024-51211-1
References Baratchi, S., Danish, H., Chheang, C., Zhou, Y., Huang, A., Lai, A., Khanmohammadi, M., Quinn, K. M., Khoshmanesh, K., & Peter, K. (2024). Piezo1 expression in neutrophils regulates shear-induced NETosis. Nature Communications, 15(1), 7023. https://doi.org/10.1038/s41467-024-51211-1
