{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T22:18:07Z","timestamp":1785449887228,"version":"3.56.0"},"reference-count":50,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2021,12,23]],"date-time":"2021-12-23T00:00:00Z","timestamp":1640217600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2022,2]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>It is unclear why activated platelets and platelet\u2010derived microparticles (MPs) accumulate in the blood of patients with systemic sclerosis (SSc). This study was undertaken to investigate whether defective phagocytosis might contribute to MP accumulation in the blood of patients with SSc.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Blood samples were obtained from a total of 81 subjects, including 25 patients with SSc and 26 patients with stable coronary artery disease (CAD). Thirty sex\u2010 and age\u2010matched healthy volunteers served as controls. Studies were also conducted in NSG mice, in which the tail vein of the mice was injected with MPs, and samples of the lung parenchyma were obtained for analysis of the pulmonary microvasculature. Tissue samples from human subjects and from mice were assessed by flow cytometry and immunochemical analyses for determination of platelet\u2013neutrophil interactions, phagocytosis, levels and distribution of P\u2010selectin, P\u2010selectin glycoprotein ligand 1 (PSGL\u20101), and HMGB1 on platelets and MPs, and concentration of byproducts of neutrophil extracellular trap (NET) generation\/catabolism.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Activated P\u2010selectin+ platelets and platelet\u2010derived HMGB1+ MPs accumulated in the blood of SSc patients but not in the blood of healthy controls. Patients with CAD, a vasculopathy independent of systemic inflammation, had fewer P\u2010selectin+ platelets and a negligible number of MPs. The expression of the receptor for P\u2010selectin, PSGL\u20101, in neutrophils from SSc patients was significantly decreased, raising the possibility that phagocytes in SSc do not recognize activated platelets, leading to a failure of phagocytosis and continued neutrophil release of MPs. As evidence of this process, activated platelets were not detected in the neutrophils from SSc patients, whereas they were consistently present in the neutrophils from patients with CAD. HMGB1+ MPs elicited generation of NETs, which were only detected in the plasma of SSc patients. In mice, P\u2010selectin\u2013PSGL\u20101 interaction resulted in platelet phagocytosis in vitro and influenced the ability of MPs to elicit NETs, endothelial activation, and migration of leukocytes through the pulmonary microvasculature.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The clearance of activated platelets via PSGL\u20101 limits the undesirable effects of MP\u2010elicited neutrophil activation. This balance is disrupted in patients with SSc. Its reconstitution might curb vascular inflammation and prevent fibrosis.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.41926","type":"journal-article","created":{"date-parts":[[2021,7,19]],"date-time":"2021-07-19T05:16:07Z","timestamp":1626671767000},"page":"318-328","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Platelet Phagocytosis via P\u2010selectin Glycoprotein Ligand 1 and Accumulation of Microparticles in Systemic Sclerosis"],"prefix":"10.1002","volume":"74","author":[{"given":"Angelo A.","family":"Manfredi","sequence":"first","affiliation":[{"name":"Universit\u00e0 Vita\u2010Salute San Raffaele and IRCCS San Raffaele Scientific Institute  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2889-366X","authenticated-orcid":false,"given":"Giuseppe A.","family":"Ramirez","sequence":"additional","affiliation":[{"name":"Universit\u00e0 Vita\u2010Salute San Raffaele and IRCCS San Raffaele Scientific Institute  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cosmo","family":"Godino","sequence":"additional","affiliation":[{"name":"Universit\u00e0 Vita\u2010Salute San Raffaele and IRCCS San Raffaele Scientific Institute  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annalisa","family":"Capobianco","sequence":"additional","affiliation":[{"name":"Universit\u00e0 Vita\u2010Salute San Raffaele and IRCCS San Raffaele Scientific Institute  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Monno","sequence":"additional","affiliation":[{"name":"Universit\u00e0 Vita\u2010Salute San Raffaele and IRCCS San Raffaele Scientific Institute  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Franchini","sequence":"additional","affiliation":[{"name":"Universit\u00e0 Vita\u2010Salute San Raffaele and IRCCS San Raffaele Scientific Institute  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrico","family":"Tombetti","sequence":"additional","affiliation":[{"name":"Universit\u00e0 Vita\u2010Salute San Raffaele and IRCCS San Raffaele Scientific Institute  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Corradetti","sequence":"additional","affiliation":[{"name":"Universit\u00e0 Vita\u2010Salute San Raffaele and IRCCS San Raffaele Scientific Institute  Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7408-9333","authenticated-orcid":false,"given":"J\u00f6rg H. 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