title: Selective abrogation of the uPA-uPAR interaction in vivo reveals a novel role in suppression of fibrin-associated inflammation.
abstract: 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.
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Connolly
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Choi
authors.forename: Henrik
authors.initials: H
authors.lastname: Gårdsvoll
authors.forename: Alexandra L
authors.initials: AL
authors.lastname: Bey
authors.forename: Brooke M
authors.initials: BM
authors.lastname: Currie
authors.forename: Triantafyllos
authors.initials: T
authors.lastname: Chavakis
authors.forename: Shihui
authors.initials: S
authors.lastname: Liu
authors.forename: Alfredo
authors.initials: A
authors.lastname: Molinolo
authors.forename: Michael
authors.initials: M
authors.lastname: Ploug
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Leppla
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Bugge
mesh_terms: 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
chemical_list: D012333:RNA, Messenger; D055293:Receptors, Urokinase Plasminogen Activator; D005337:Fibrin; D014568:Urokinase-Type Plasminogen Activator
references.citation: Blood. 1998 Mar 1;91(5):1616-24
references.pmid: 9473227
references.citation: J Biol Chem. 2000 Jul 21;275(29):21785-8
references.pmid: 10801897
references.citation: J Biol Chem. 1989 Jan 15;264(2):1180-9
references.pmid: 2536017
references.citation: Blood. 2008 Apr 1;111(7):3607-14
references.pmid: 18239087
references.citation: Blood. 1997 Aug 1;90(3):958-66
references.pmid: 9242524
references.citation: J Biol Chem. 2006 Jul 14;281(28):19260-72
references.pmid: 16672229
references.citation: Int Immunol. 1993 Aug;5(8):957-64
references.pmid: 8398989
references.citation: J Biol Chem. 1989 Feb 5;264(4):2185-8
references.pmid: 2521625
references.citation: Proc Natl Acad Sci U S A. 2003 Jan 21;100(2):657-62
references.pmid: 12525700
references.citation: Nat Rev Mol Cell Biol. 2002 Dec;3(12):932-43
references.pmid: 12461559
references.citation: EMBO J. 2000 Sep 1;19(17):4817-26
references.pmid: 10970872
references.citation: J Clin Invest. 2004 Jan;113(1):38-48
references.pmid: 14702107
references.citation: Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):15143-8
references.pmid: 10611352
references.citation: Am J Pathol. 2005 Sep;167(3):721-32
references.pmid: 16127152
references.citation: J Exp Med. 2001 May 21;193(10):1123-33
references.pmid: 11369784
references.citation: Nature. 1994 Mar 31;368(6470):419-24
references.pmid: 8133887
references.citation: Genes Dev. 2008 Jul 1;22(13):1747-52
references.pmid: 18593877
references.citation: Genes Dev. 1995 Apr 1;9(7):794-807
references.pmid: 7705657
references.citation: Cell. 1996 Nov 15;87(4):709-19
references.pmid: 8929539
references.citation: J Clin Invest. 2007 Nov;117(11):3224-35
references.pmid: 17932565
references.citation: Nat Rev Mol Cell Biol. 2010 Jan;11(1):23-36
references.pmid: 20027185
references.citation: Crit Rev Oncol Hematol. 1986;4(3):249-301
references.pmid: 2420482
references.citation: Blood. 2006 Nov 1;108(9):3021-6
references.pmid: 16849641
references.citation: Science. 2008 Nov 14;322(5904):1101-4
references.pmid: 19008446
references.citation: Ophthalmology. 1987 Aug;94(8):949-59
references.pmid: 3658371
references.citation: J Cell Biol. 2007 Jun 18;177(6):1119-32
references.pmid: 17576803
references.citation: BMC Gastroenterol. 2006 Nov 29;6:40
references.pmid: 17134505
references.citation: Br Dent J. 2004 Oct 23;197(8):467-8
references.pmid: 15547600
references.citation: Am J Ophthalmol. 2002 Apr;133(4):451-5
references.pmid: 11931777
references.citation: J Clin Invest. 1993 Dec;92(6):2746-55
references.pmid: 8254028
references.citation: J Biol Chem. 2001 May 25;276(21):17976-84
references.pmid: 11278833
references.citation: Nat Med. 1996 Mar;2(3):287-92
references.pmid: 8612226
references.citation: J Clin Invest. 1996 Feb 1;97(3):870-8
references.pmid: 8609247
references.citation: Circulation. 1995 Nov 1;92(9):2585-93
references.pmid: 7586361
references.citation: J Biol Chem. 2010 Apr 2;285(14):10982-92
references.pmid: 20133942
references.citation: Eur J Pediatr. 2003 Jul;162(7-8):462-465
references.pmid: 12719968
references.citation: Am J Physiol Cell Physiol. 2007 Oct;293(4):C1278-85
references.pmid: 17652428
references.citation: Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6698-703
references.pmid: 15096619
references.citation: Int J Gynecol Pathol. 2004 Jul;23(3):292-5
references.pmid: 15213608
references.citation: J Cell Biol. 2007 Sep 10;178(6):1039-51
references.pmid: 17785520
references.citation: Proc Natl Acad Sci U S A. 1996 Jun 11;93(12):5899-904
references.pmid: 8650190
references.citation: N Engl J Med. 1998 Dec 3;339(23):1679-86
references.pmid: 9834305
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 10;104(28):11814-9
references.pmid: 17606926
references.citation: Am J Physiol Renal Physiol. 2001 Dec;281(6):F1157-63
references.pmid: 11704568
references.citation: APMIS. 1999 Jan;107(1):120-7
references.pmid: 10190288
references.citation: Science. 2006 Feb 3;311(5761):656-9
references.pmid: 16456079
references.citation: J Clin Invest. 2004 Jun;113(11):1596-606
references.pmid: 15173886
references.citation: J Cell Biol. 1998 Jan 12;140(1):233-45
references.pmid: 9425170
references.citation: J Biol Chem. 1995 Jul 14;270(28):16886-94
references.pmid: 7622505