Activated Platelet–Released Heat Shock Protein 90α Triggers Autophagy‐Dependent Neutrophil Extracellular Trap Formation and Amplifies Sepsis

Platelets are crucial to the development of thrombosis and coagulation abnormalities in sepsis, but the mechanisms by which they contribute to these pathological processes are not fully understood. Here, we identify a key role for platelet-released heat shock protein 90α (HSP90α) in driving neutrophil extracellular trap (NET) formation and supporting thromboinflammation during sepsis. Proteomic analysis of platelets from patients with sepsis showed a significant increase in HSP90α, which we traced back to trafficking pathways originating from megakaryocytes. When activated, platelets translocate HSP90α to their plasma membrane and release it into the extracellular space in both free and exosome-associated forms. Extracellular HSP90α acts as a damage-associated molecular pattern that binds to toll-like receptor 4 (TLR4) on neutrophils. This binding activates a downstream MyD88-Beclin 1 signaling pathway, triggering autophagy and leading to NET formation. Blocking extracellular HSP90α with a neutralizing monoclonal antibody significantly reduced NET formation both in vitro and in vivo, resulting in decreased sepsis-related thrombosis and inflammation. This platelet-HSP90α-TLR4-autophagy-NET pathway not only deepens our understanding of platelet-induced immunothrombosis but also suggests potential targets for therapies aimed at reducing coagulation problems and organ failure in septic patients.