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.
Haematologica. 2018 Jul;103(7):1235-1244. doi: 10.3324/haematol.2017.185637. Epub 2018 Apr 19.
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. , 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. , 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.
血小板脱颗粒对于止血至关重要，并且可能参与炎症反应。血小板中的胞吐作用是由 SNARE 蛋白介导的，应该由 Munc13 蛋白控制。我们发现血小板表达 Munc13-2 和 -4。我们评估了 Munc13-2 和 -4 全局和条件敲除 (KO) 小鼠的血小板颗粒胞吐作用，观察到 Munc13-4 的缺失会使致密颗粒释放受损，并间接影响α颗粒的胞吐作用。我们没有发现 Munc13-2 在血小板中具有胞吐作用，即使在没有 Munc13-4 的情况下也是如此。Munc13-4 缺陷型血小板在低剂量胶原存在下聚集功能受损。在流动室测定中，我们观察到 Munc13-4 作为血栓形成的限速因素。进一步研究发现，血小板中 Munc13-4 的表达与静脉出血时间和动脉血栓形成时间之间存在剂量依赖性关系。最后，在变应性气道炎症模型中，我们发现血小板特异性 Munc13-4 KO 小鼠的气道高反应性和嗜酸性粒细胞炎症减轻。综上所述，我们的研究结果表明，Munc13-4 依赖性血小板致密颗粒释放在止血、血栓形成和变应性炎症中发挥着重要作用。
