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Published on: April 13, 2018
Kindlin-3 in platelets and myeloid cells differentially regulates deep vein thrombosis in mice
Yanyan Yan1, Hongqin Yang1, Xiao Hu1
1Collaborative Research Program for Cell Adhesion Molecules, Shanghai University School of Life Sciences, Shanghai, China.
Abstract:
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.
Insights
Kindlin-3 in platelets suppresses deep vein thrombosis (DVT), while its absence in myeloid cells enhances DVT by increasing neutrophil extracellular traps (NETs). This reveals distinct roles for kindlin-3 in thrombosis regulation.
Area of Science:
- Hematology
- Thrombosis Research
- Cellular Biology
Background:
- Platelets and myeloid cells are crucial for deep vein thrombosis (DVT) development.
- Kindlin-3 acts as a key integrin activator in these blood cells.
- The specific roles of kindlin-3 in different cell types during DVT remain unclear.
Purpose of the Study:
- To investigate the role of kindlin-3 in regulating stenosis-induced deep vein thrombosis (DVT) in mice.
- To elucidate the distinct functions of kindlin-3 in platelets versus myeloid cells in DVT pathogenesis.
- To uncover the underlying mechanisms by which kindlin-3 influences DVT, particularly concerning neutrophil extracellular traps (NETs).
Main Methods:
- Utilized genetically modified mouse models with specific deficiencies in kindlin-3 in platelets (Kindlin-3fl/flPF4-Cre) and myeloid cells (Kindlin-3fl/flLysM-Cre).
- Induced deep vein thrombosis (DVT) via inferior vena cava (IVC) stenosis.
- Quantified plasma levels of neutrophil extracellular traps (NETs) and assessed DVT progression.
- Administered DNase I and a PAD4 inhibitor to evaluate their impact on DVT in the context of kindlin-3 deficiency.
Main Results:
- Mice with a defective kindlin-3 mutant showed suppressed DVT, confirming kindlin-3's requirement for integrin signaling in DVT.
- Platelet-specific deficiency of kindlin-3 significantly suppressed DVT.
- Conversely, myeloid cell-specific deficiency of kindlin-3 markedly enhanced early DVT development.
- Elevated plasma NET levels were observed in myeloid-deficient kindlin-3 mice, which were reduced by DNase I or PAD4 inhibitor treatment.
- Kindlin-3-integrin αIIbβ3 signaling in platelets was essential for promoting NET release.
Conclusions:
- Kindlin-3 plays differential roles in platelets and myeloid cells in regulating DVT.
- Kindlin-3 in myeloid cells, particularly neutrophils, restrains NET release, thereby inhibiting DVT.
- Kindlin-3 in platelets promotes DVT, partly by facilitating NET release.
- These findings provide novel mechanistic insights into DVT pathogenesis and the dual role of kindlin-3.
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