Research Paper Volume 11, Issue 17 pp 6951—6959
Kindlin-3 in platelets and myeloid cells differentially regulates deep vein thrombosis in mice
- 1 Collaborative Research Program for Cell Adhesion Molecules, Shanghai University School of Life Sciences, Shanghai, China
- 2 Blood Research Institute, Versiti, Milwaukee, WI 53213, USA
- 3 Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
- 4 Department of Biochemistry, Medical College of Milwaukee, WI 53226, USA
received: June 17, 2019 ; accepted: August 16, 2019 ; published: August 31, 2019 ;https://doi.org/10.18632/aging.102229
How to Cite
Copyright © 2019 Yan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Platelets and myeloid cells cooperate to promote deep vein thrombosis (DVT). Here we evaluated the role of kindlin-3, a key integrin activator in these cells, in regulating stenosis-induced DVT in mice. DVT was significantly suppressed in mice that express a kindlin-3 mutant defective for integrin binding, showing that kindlin-3-mediated integrin signaling in blood cells is required for DVT. While platelet-specific deficiency of kindlin-3 in Kindlin-3fl/flPF4-Cre mice significantly suppressed DVT, deficiency of kindlin-3 specifically in myeloid cells in Kindlin-3fl/flLysM-Cre mice remarkably enhanced the early development of DVT, indicating that kindlin-3 in platelets and myeloid cells can play distinct roles in regulating DVT. Mechanistically, the levels of neutrophil extracellular traps (NETs) in plasma, a key DVT facilitator, were significantly elevated in Kindlin-3fl/flLysM-Cre mice upon the IVC stenosis; and treatment with either DNase I or PAD4 inhibitor could effectively compromise the enhancement of DVT in these mice, suggesting that kindlin-3 in neutrophils may affect DVT via restraining NET release. In addition, we found that the kindlin-3-integrin αIIbβ3 signaling in platelets was required to promote NET release. Together, our studies reveal that kindlin-3 in platelets and myeloid cells can differentially regulate DVT through orchestrating NET release, thus providing further mechanistic insights into DVT.
DVT: deep vein thrombosis; NET: Neutrophil extracellular traps; K3KI: Kindlin-3 knock-in; IVC: Inferior vena cava.