Platelet glycoprotein VI in platelet-neutrophil interactions: From complex formation to neutrophil extracellular trap-associated pathology.

Platelets and neutrophils form dynamic platelet-neutrophil complexes (PNCs) that connect vascular injury with inflammatory effector responses. Glycoprotein VI (GPVI), a platelet-restricted immunoreceptor, converts collagen- and fibrin-related cues into ITAM signaling, granule secretion and integrin activation. GPVI is not known to function as a direct platelet-neutrophil adhesion receptor. Instead, GPVI-dependent platelet activation generates an adhesive and secretory platelet phenotype that favors PNC formation through P-selectin/PSGL-1, GPIbα/Mac-1, integrin-dependent bridging, and soluble mediators. Once formed, PNCs can enhance neutrophil recruitment and activation and, under permissive inflammatory conditions, may promote NET formation. Neutrophil extracellular traps (NETs) may then provide procoagulant scaffolds that amplify vascular inflammation and tissue injury. This review synthesizes the mechanistic steps linking GPVI signaling to PNC formation and NET release and evaluates evidence for this framework in acute lung injury and sepsis, sterile inflammation and autoimmune disease, cardiovascular thrombosis, and cancer-associated thrombosis and metastasis. Together, these findings suggest that GPVI sits upstream of platelet-neutrophil interactions and links platelet activation to neutrophil effector responses.