Kindlin-3 in platelets and myeloid cells differentially regulates deep vein thrombosis in mice

• Published in: Aging (Albany, NY.) NY.), 2019-08, Vol.11 (17), p.6951-6959
• Main Authors: Yan, Yanyan, Yang, Hongqin, Hu, Xiao, Zhang, Zeping, Ge, Shushu, Xu, Zhen, Gao, Juan, Liu, Junling, White, Gilbert C, Ma, Yan-Qing
• Format: Article
• Language: English
• Subjects: Research Paper
• ISSN: 1945-4589; 1945-4589
• DOI: 10.18632/aging.102229

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 PF4-Cre mice significantly suppressed DVT, deficiency of kindlin-3 specifically in myeloid cells in Kindlin-3 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 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.