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Platelet phagocytosis via PSGL1 and accumulation of microparticles in systemic sclerosis. OBJECTIVES: It is unclear why activated platelets and platelet-derived microparticles (µPs) accumulate in the blood of patients with systemic sclerosis (SSc). Here we investigated whether defective phagocytosis might contribute. METHODS: Platelet-neutrophil interaction, phagocytosis, P-selectin, PSGL-1, HMGB1 expression and distribution on platelet and µPs, the concentration of byproducts of NET generation/catabolism were assessed by flow cytometry and immunochemistry in 81 donors. 25 patients had SSc, 26 patients stable coronary artery atherosclerosis (CAD). 30 sex- and age-matched healthy volunteers served as controls. Lung parenchyma and microvasculature were assessed in NSG mice after µPs injection in the tail vein. RESULTS: Activated P-selectin+ platelets and platelet-derived-HMGB1+ µPs accumulate in the blood of SSc patients and not of controls. Patients with CAD, a vasculopathy independent of systemic inflammation, had less P-selectin+ platelets and negligible µPs. The expression of the receptor for P-selectin, PSGL-1 in SSc neutrophils was significantly decreased, raising the possibility that phagocytes fail to recognize and phagocytose activated platelets, which in turn might keep releasing µPs. In support, SSc neutrophils did not contain platelets, consistently present within CAD neutrophils. HMGB1+ µPs elicit the generation of NETs, which were detected in the plasma of SSc patients only. P-selectin/PSGL-1 interaction resulted in platelet phagocytosis in vitro and influenced the µPs ability to elicit NETs, endothelial activation and migration of leukocytes through pulmonary microvasculature in mice. CONCLUSIONS: The clearance of activated platelets via PSGL-1 limits undesirable effects of µPs-elicited neutrophil activation. This balance is disrupted in patients with SSc. Its reconstitution might curb vascular inflammation and prevent fibrosis.