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Kindlin-3 in platelets and myeloid cells differentially regulates deep vein thrombosis in mice
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 b...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756892/ https://www.ncbi.nlm.nih.gov/pubmed/31477636 http://dx.doi.org/10.18632/aging.102229 |
Sumario: | 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-3(fl/fl)PF4-Cre mice significantly suppressed DVT, deficiency of kindlin-3 specifically in myeloid cells in Kindlin-3(fl/fl)LysM-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-3(fl/fl)LysM-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. |
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