Platelet Munc13-4 regulates hemostasis, thrombosis and airway inflammation
Autor: | Keegan Breaux, Michael J. Tuvim, Roberto Adachi, Eduardo I. Cardenas, Jose R. Flores, Rolando E. Rumbaut, Marco A. Ramos, Qi Da, Alan R. Burns |
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Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Blood Platelets Inflammation Exocytosis Article Allergic inflammation Platelet Biology & its Disorders 03 medical and health sciences Mice Platelet degranulation medicine Hypersensitivity Animals Platelet Platelet activation Mice Knockout Hemostasis Chemistry Secretory Vesicles Membrane Proteins Thrombosis Hematology Platelet Activation 3. Good health Cell biology Disease Models Animal 030104 developmental biology Alpha Granule Disease Susceptibility medicine.symptom Dense granule Biomarkers |
Zdroj: | Haematologica |
ISSN: | 1592-8721 |
Popis: | Platelet degranulation is crucial for hemostasis and may participate in inflammation. Exocytosis in platelets is mediated by SNARE proteins and should be controlled by Munc13 proteins. We found that platelets express Munc13-2 and -4. We assessed platelet granule exocytosis in Munc13-2 and -4 global and conditional knockout (KO) mice, and observed that deletion of Munc13-4 ablates dense granule release and indirectly impairs alpha granule exocytosis. We found no exocytic role for Munc13-2 in platelets, not even in the absence of Munc13-4. In vitro, Munc13-4-deficient platelets exhibited defective aggregation at low doses of collagen. In a flow chamber assay, we observed that Munc13-4 acted as a rate-limiting factor in the formation of thrombi. In vivo, we observed a dose-dependency between Munc13-4 expression in platelets and both venous bleeding time and time to arterial thrombosis. Finally, in a model of allergic airway inflammation, we found that platelet-specific Munc13-4 KO mice had a reduction in airway hyper-responsiveness and eosinophilic inflammation. Taken together, our results indicate that Munc13-4-dependent platelet dense granule release plays essential roles in hemostasis, thrombosis and allergic inflammation. |
Databáze: | OpenAIRE |
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