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The lectin-like domain of thrombomodulin interferes with complement activation and protects against arthritis

Van de Wouwer, M. ; Plaisance, S. ; De Vriese, A. ; Waelkens, E. ; Collen, D. ; Persson, Jenny J LU ; Daha, M. R. and Conway, E. M. (2006) In Journal of Thrombosis and Haemostasis 4(8). p.1813-1824
Abstract
Background: Thrombomodulin (TM) is predominantly a vascular endothelial cell plasma membrane glycoprotein that, via distinct structural domains, interacts with multiple ligands, thereby modulating coagulation, fibrinolysis, complement activation, inflammation and cell proliferation. We previously reported that by mediating signals that interfere with mitogen-activated protein kinase and nuclear factor kappa B pathways, the amino-terminal C-type lectin-like domain of TM has direct anti-inflammatory properties. Methods: In the current study, we use murine models of acute inflammatory arthritis and biochemical approaches to assess the mechanism by which the lectin-like domain of TM modifies disease progression. Results: Mice lacking the... (More)
Background: Thrombomodulin (TM) is predominantly a vascular endothelial cell plasma membrane glycoprotein that, via distinct structural domains, interacts with multiple ligands, thereby modulating coagulation, fibrinolysis, complement activation, inflammation and cell proliferation. We previously reported that by mediating signals that interfere with mitogen-activated protein kinase and nuclear factor kappa B pathways, the amino-terminal C-type lectin-like domain of TM has direct anti-inflammatory properties. Methods: In the current study, we use murine models of acute inflammatory arthritis and biochemical approaches to assess the mechanism by which the lectin-like domain of TM modifies disease progression. Results: Mice lacking the lectin-like domain of TM (TM(LeD/LeD)mice) develop inflammatory arthritis that is more rapid in onset and more severe than that developed in their wildtype counterparts. In two models of arthritis, treatment of mice with recombinant soluble lectin-like domain of TM significantly suppresses clinical evidence of disease and diminishes monocyte/macrophage infiltration into the synovium, with weaker expression of the pro-inflammatory high mobility group box chromosomal protein 1. While thrombin-TM mediated activation of thrombin activatable fibrinolysis inhibitor inactivates complement factors C3a and C5a, we show that TM has a second independent mechanism to regulate complement: the lectin-like domain of TM directly interferes with complement activation via the classical and lectin pathways. Conclusions: These data extend previous insights into the mechanisms by which TM modulates innate immunity, and highlight its potential as a therapeutic target for inflammatory diseases. (Less)
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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
thrombin, synovium, inflammation, coagulation, endothelial cell, thrombin activatable fibrinolysis inhibitor
in
Journal of Thrombosis and Haemostasis
volume
4
issue
8
pages
1813 - 1824
publisher
Wiley-Blackwell
external identifiers
  • wos:000239335200023
  • scopus:33746636356
ISSN
1538-7933
DOI
10.1111/j.1538-7836.2006.02033.x
language
English
LU publication?
yes
id
fcd4ef03-6af2-4649-be35-bc2e8bda11e8 (old id 399430)
date added to LUP
2016-04-01 11:53:37
date last changed
2020-12-15 02:59:36
@article{fcd4ef03-6af2-4649-be35-bc2e8bda11e8,
  abstract     = {Background: Thrombomodulin (TM) is predominantly a vascular endothelial cell plasma membrane glycoprotein that, via distinct structural domains, interacts with multiple ligands, thereby modulating coagulation, fibrinolysis, complement activation, inflammation and cell proliferation. We previously reported that by mediating signals that interfere with mitogen-activated protein kinase and nuclear factor kappa B pathways, the amino-terminal C-type lectin-like domain of TM has direct anti-inflammatory properties. Methods: In the current study, we use murine models of acute inflammatory arthritis and biochemical approaches to assess the mechanism by which the lectin-like domain of TM modifies disease progression. Results: Mice lacking the lectin-like domain of TM (TM(LeD/LeD)mice) develop inflammatory arthritis that is more rapid in onset and more severe than that developed in their wildtype counterparts. In two models of arthritis, treatment of mice with recombinant soluble lectin-like domain of TM significantly suppresses clinical evidence of disease and diminishes monocyte/macrophage infiltration into the synovium, with weaker expression of the pro-inflammatory high mobility group box chromosomal protein 1. While thrombin-TM mediated activation of thrombin activatable fibrinolysis inhibitor inactivates complement factors C3a and C5a, we show that TM has a second independent mechanism to regulate complement: the lectin-like domain of TM directly interferes with complement activation via the classical and lectin pathways. Conclusions: These data extend previous insights into the mechanisms by which TM modulates innate immunity, and highlight its potential as a therapeutic target for inflammatory diseases.},
  author       = {Van de Wouwer, M. and Plaisance, S. and De Vriese, A. and Waelkens, E. and Collen, D. and Persson, Jenny J and Daha, M. R. and Conway, E. M.},
  issn         = {1538-7933},
  language     = {eng},
  number       = {8},
  pages        = {1813--1824},
  publisher    = {Wiley-Blackwell},
  series       = {Journal of Thrombosis and Haemostasis},
  title        = {The lectin-like domain of thrombomodulin interferes with complement activation and protects against arthritis},
  url          = {http://dx.doi.org/10.1111/j.1538-7836.2006.02033.x},
  doi          = {10.1111/j.1538-7836.2006.02033.x},
  volume       = {4},
  year         = {2006},
}