The lectin-like domain of thrombomodulin interferes with complement activation and protects against arthritis.
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 kappaB 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.
Van de Wouwer
M
M
Center for Transgene Technology and Gene Therapy, University of Leuven, Leuven, Belgium.
Plaisance
S
S
De Vriese
A
A
Waelkens
E
E
Collen
D
D
Persson
J
J
Daha
M R
MR
Conway
E M
EM
D000818:Animals; D001168:Arthritis / Q000378:metabolism* / Q000517:prevention & control; D001169:Arthritis, Experimental / Q000378:metabolism; D001777:Blood Coagulation; D025901:Carboxypeptidase B2 / Q000378:metabolism*; D003167:Complement Activation; D018014:Gene Transfer Techniques; D006801:Humans; D007249:Inflammation; D037102:Lectins / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D017434:Protein Structure, Tertiary; D013583:Synovial Membrane / Q000473:pathology; D013917:Thrombin / Q000378:metabolism; D018180:Thrombomodulin / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism
D037102:Lectins; D018180:Thrombomodulin; D025901:Carboxypeptidase B2; D013917:Thrombin