Selective abrogation of the uPA-uPAR interaction in vivo reveals a novel role in suppression of fibrin-associated inflammation.
The urokinase plasminogen activator receptor (uPAR) has emerged as a potential regulator of cell adhesion, cell migration, proliferation, differentiation, and cell survival in multiple physiologic and pathologic contexts. The urokinase plasminogen activator (uPA) was the first identified ligand for uPAR, but elucidation of the specific functions of the uPA-uPAR interaction in vivo has been difficult because uPA has important physiologic functions that are independent of binding to uPAR and because uPAR engages multiple ligands. Here, we developed a new mouse strain (Plau(GFDhu/GFDhu)) in which the interaction between endogenous uPA and uPAR is selectively abrogated, whereas other functions of both the protease and its receptor are retained. Specifically, we introduced 4 amino acid substitutions into the growth factor domain (GFD) of uPA that abrogate uPAR binding while preserving the overall structure of the domain. Analysis of Plau(GFDhu/GFDhu) mice revealed an unanticipated role of the uPA-uPAR interaction in suppressing inflammation secondary to fibrin deposition. In contrast, leukocyte recruitment and tissue regeneration were unaffected by the loss of uPA binding to uPAR. This study identifies a principal in vivo role of the uPA-uPAR interaction in cell-associated fibrinolysis critical for suppression of fibrin accumulation and fibrin-associated inflammation and provides a valuable model for further exploration of this multifunctional receptor.
Connolly
Brian M
BM
Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
Choi
Eun Young
EY
Gårdsvoll
Henrik
H
Bey
Alexandra L
AL
Currie
Brooke M
BM
Chavakis
Triantafyllos
T
Liu
Shihui
S
Molinolo
Alfredo
A
Ploug
Michael
M
Leppla
Stephen H
SH
Bugge
Thomas H
TH
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005260:Female; D005337:Fibrin / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008099:Liver / Q000276:immunology / Q000293:injuries / Q000378:metabolism; D055370:Lung Injury / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011014:Pneumonia / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D012333:RNA, Messenger / Q000235:genetics; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012871:Skin Diseases / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D015996:Survival Rate; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D014945:Wound Healing
D012333:RNA, Messenger; D055293:Receptors, Urokinase Plasminogen Activator; D005337:Fibrin; D014568:Urokinase-Type Plasminogen Activator
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