Neutrophil-Mediated Proteolysis of Thrombospondin-1 Promotes Platelet Adhesion and String Formation
| Autor: | Nahla Ibrahim, Lisa-Marie Mauracher, Lejla Alidzanovic, Lena Hell, Bernd Jilma, Alice Assinger, Ulrich Budde, Johannes A. Schmid, Manuel Salzmann, Ingrid Pabinger, Barbara Tischler, Sabine Rauscher, Christine Brostjan, Patrick Starlinger, Katharina Seif, Branislav Zagrapan |
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| Rok vydání: | 2018 |
| Předmět: |
Blood Platelets
0301 basic medicine proteolysis endocrine system Proteases Platelet Aggregation Neutrophils Proteolysis cathepsin G 030204 cardiovascular system & hematology Cathepsin G Thrombospondin 1 Mice 03 medical and health sciences chemistry.chemical_compound Platelet Adhesiveness 0302 clinical medicine Von Willebrand factor immune system diseases von Willebrand Factor Cellular Haemostasis and Platelets medicine Animals Humans Platelet thrombospondin-1 Cells Cultured Mice Knockout Hemostasis biology medicine.diagnostic_test Elastase platelet string formation virus diseases Hematology Neutrophil extracellular traps Coculture Techniques Cell biology Mice Inbred C57BL 030104 developmental biology chemistry biology.protein platelet adhesion Endothelium Vascular Protein Multimerization neutrophil elastase |
| Zdroj: | Thrombosis and Haemostasis |
| ISSN: | 2567-689X 0340-6245 |
| DOI: | 10.1055/s-0038-1675229 |
| Popis: | Thrombospondin-1 (TSP-1) is primarily expressed by platelets and endothelial cells (ECs) and rapidly released upon their activation. It functions in haemostasis as a bridging molecule in platelet aggregation, by promoting platelet adhesion to collagen and by protecting von Willebrand factor strings from degradation. In blood of patients undergoing surgery and in co-cultures of neutrophils with platelets or ECs, we observed proteolysis of the 185 kDa full-length TSP-1 to a 160-kDa isoform. We hypothesized that TSP-1 processing may alter its haemostatic properties. Selective enzyme inhibitors in co-cultures revealed that neutrophil proteases elastase and cathepsin G mediate TSP-1 processing. The cut site of cathepsin G was mapped to TSP-1 amino acids R237/T238 by Edman sequencing. Formation of neutrophil extracellular traps protected TSP-1 from complete degradation and promoted controlled processing to the 160-kDa isoform. Haemostatic properties were tested by platelet aggregation, adhesion, coagulation and string formation under flow. Platelets from TSP-1 deficient mice did not differ from wild-type in platelet aggregation but showed severe impairment of platelet adhesion to collagen and string formation under flow. Reconstitution experiments revealed that the 160-kDa TSP-1 isoform was markedly more potent than the 185-kDa full-length molecule in restoring function. Thus, TSP-1 processing by neutrophil proteases yields a 160-kDa isoform which shows enhanced potency to promote platelet adhesion and string formation. This finding reveals a novel mechanism of neutrophil-mediated thrombus formation and provides first evidence for the impact of TSP-1 proteolysis on its haemostatic properties. |
| Databáze: | OpenAIRE |
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