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Fibrin-VLDL receptor-dependent pathway promotes leukocyte transmigration by inhibiting Src kinase Fyn and is a target for fibrin β15–42 peptide

Authors
  • Yakovlev, Sergiy1, 2
  • Cao, Chunzhang1, 3
  • Galisteo, Rebeca1
  • Zhang, Li1, 3
  • Strickland, Dudley K.1, 3, 4
  • Medved, Leonid1, 2
  • 1 Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD
  • 2 Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD
  • 3 Department of Physiology, University of Maryland School of Medicine, Baltimore, MD
  • 4 Department of Surgery, University of Maryland School of Medicine, Baltimore, MD
Type
Published Article
Journal
Thrombosis and Haemostasis
Publisher
Georg Thieme Verlag KG
Publication Date
Aug 29, 2019
Volume
119
Issue
11
Pages
1816–1826
Identifiers
DOI: 10.1055/s-0039-1695008
PMID: 31466086
PMCID: PMC7179994
Source
PubMed Central
Keywords
License
Unknown

Abstract

According to the current view, binding of fibrin degradation product E1 fragment to endothelial VE-cadherin promotes transendothelial migration of leukocytes and thereby inflammation, and fibrin-derived β15–42 peptide reduces leukocyte transmigration by competing with E1 for binding to VE-cadherin and, in addition, by signaling through Src kinase Fyn. However, the very low affinity of β15–42 to VE-cadherin raised a question about its ability to inhibit E1-VE-cadherin interaction. Further, our previous study revealed that fibrin promotes leukocyte transmigration through the VLDL receptor (VLDLR)-dependent pathway and suggested a possible link between the inhibitory properties of β15–42 and this pathway. To test such a link and the proposed inhibitory mechanisms for β15–42, we performed in vitro experiments using SPR, ELISA, and leukocyte transendothelial migration assay, and in vivo studies with wild-type and VLDLR-deficient mice using mouse model of peritonitis. The experiments revealed that β15–42 cannot inhibit E1-VE-cadherin interaction at the concentrations used in the previous in vivo studies leaving the proposed Fyn-dependent signaling mechanism as a viable explanation for the inhibitory effect of β15–42. While testing this mechanism, we confirmed that Fyn plays a critical role in controlling fibrin-induced transendothelial migration of leukocytes and found that signaling through the VLDLR-dependent pathway results in inhibition of Fyn thereby increasing leukocyte transmigration. Furthermore, our in vivo experiments revealed that β15–42 inhibits this pathway thereby preventing inhibition of Fyn and reducing leukocyte transmigration. Thus, this study clarifies the molecular mechanism underlying the VLDLR-dependent pathway of leukocyte transmigration and reveals that this pathway is a target for β15–42.

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