Platelet Munc13-4 regulates hemostasis, thrombosis and airway inflammation
Eduardo I. Cardenas,
Keegan Breaux,
Qi Da,
Jose R. Flores,
Marco A. Ramos,
Michael J. Tuvim,
Alan R. Burns,
Rolando E. Rumbaut,
Roberto Adachi
Affiliations
Eduardo I. Cardenas
Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;Tecnologico de Monterrey, Escuela de Ingenieria y Ciencias, Monterrey, Mexico
Keegan Breaux
Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Qi Da
Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA;Department of Medicine, Baylor College of Medicine, Houston, TX, USA
Jose R. Flores
Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Marco A. Ramos
Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Michael J. Tuvim
Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Alan R. Burns
College of Optometry, University of Houston, TX, USA
Rolando E. Rumbaut
Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA;Department of Medicine, Baylor College of Medicine, Houston, TX, USA
Roberto Adachi
Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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.
