Directed transport of neutrophil-derived extracellular vesicles enables platelet-mediated innate immune response

Abstract

The innate immune response to bacterial infections requires the interaction of neutrophils and platelets. Here, we show that a multistep reciprocal crosstalk exists between these two cell types, ultimately facilitating neutrophil influx into the lung to eliminate infections. Activated platelets adhere to intravascular neutrophils through P-selectin/P-selectin glycoprotein ligand-1 (PSGL-1)-mediated binding, a primary interaction that allows platelets glycoprotein Ibα (GPIbα)-induced generation of neutrophil-derived extracellular vesicles (EV). EV production is directed by exocytosis and allows shuttling of arachidonic acid into platelets. EVs are then specifically internalized into platelets in a Mac1-dependent fashion, and relocated into intracellular compartments enriched in cyclooxygenase1 (Cox1), an enzyme processing arachidonic acid to synthesize thromboxane A2 (TxA2). Finally, platelet-derived-TxA2 elicits a full neutrophil response by inducing the endothelial expression of ICAM-1, intravascular crawling, and extravasation. We conclude that critical substrate–enzyme pairs are compartmentalized in neutrophils and platelets during steady state limiting non-specific inflammation, but bacterial infection triggers regulated EV shuttling resulting in robust inflammation and pathogen clearance.

Amicus or Adversary Revisited: Platelets in Acute Lung Injury and Acute Respiratory Distress Syndrome

“…Expanding on the theme of platelet-neutrophil interaction, another group reported intricate reciprocal signaling between the two cell types. Platelet depletion reduced lung microvascular platelet-neutrophil aggregate formation, neutrophils in BAL samples, and survival in a mouse model of Escherichia coli pneumonia (39). Activated platelets adhered to neutrophils via P-selectin interacting with PSGL-1; this facilitated the formation of neutrophil microparticles (microvesicles) in a platelet GPIba-dependent fashion.…”

Application of Extracellular Vesicles Proteomics to Cardiovascular Disease: Guidelines, Data Analysis, and Future Perspectives

“…There are many similarities between the complement and coagulation systems, both being characterized by sequential activation of a series of proteins . In this context, recent studies have described that EVs have multiple roles in promoting the coagulation cascade and the immune modulation . Complement cascade proteins are well known to predict the risk of future cardiovascular events.…”

Neutrophils as effectors of vascular inflammation

“…Although platelet‐neutrophil interactions are clearly major drivers of thrombo‐inflammatory injury in the vasculature, crosstalk with platelets is also required for neutrophils to properly exert their pathogen‐clearing functions. In a model of experimental pneumonia, neutrophils provided arachidonic acid to platelets through extracellular vesicles, and these lipids were in turn substrate for the generation of TxA 2 , which enhanced endothelial expression of adhesion molecule ICAM‐1 to further amplify leucocyte recruitment …”