The urokinase receptor (uPAR) facilitates clearance of Borrelia burgdorferi.
The causative agent of Lyme borreliosis, the spirochete Borrelia burgdorferi, has been shown to induce expression of the urokinase receptor (uPAR); however, the role of uPAR in the immune response against Borrelia has never been investigated. uPAR not only acts as a proteinase receptor, but can also, dependently or independently of ligation to uPA, directly affect leukocyte function. We here demonstrate that uPAR is upregulated on murine and human leukocytes upon exposure to B. burgdorferi both in vitro as well as in vivo. Notably, B. burgdorferi-inoculated C57BL/6 uPAR knock-out mice harbored significantly higher Borrelia numbers compared to WT controls. This was associated with impaired phagocytotic capacity of B. burgdorferi by uPAR knock-out leukocytes in vitro. B. burgdorferi numbers in vivo, and phagocytotic capacity in vitro, were unaltered in uPA, tPA (low fibrinolytic activity) and PAI-1 (high fibrinolytic activity) knock-out mice compared to WT controls. Strikingly, in uPAR knock-out mice partially backcrossed to a B. burgdorferi susceptible C3H/HeN background, higher B. burgdorferi numbers were associated with more severe carditis and increased local TLR2 and IL-1beta mRNA expression. In conclusion, in B. burgdorferi infection, uPAR is required for phagocytosis and adequate eradication of the spirochete from the heart by a mechanism that is independent of binding of uPAR to uPA or its role in the fibrinolytic system.
Hovius
Joppe W R
JW
Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam, AMC, Amsterdam, The Netherlands. j.w.hovius@amc.uva.nl
Bijlsma
Maarten F
MF
van der Windt
Gerritje J W
GJ
Wiersinga
W Joost
WJ
Boukens
Bastiaan J D
BJ
Coumou
Jeroen
J
Oei
Anneke
A
de Beer
Regina
R
de Vos
Alex F
AF
van 't Veer
Cornelis
C
van Dam
Alje P
AP
Wang
Penghua
P
Fikrig
Erol
E
Levi
Marcel M
MM
Roelofs
Joris J T H
JJ
van der Poll
Tom
T
D000818:Animals; D001170:Arthritis, Infectious / Q000382:microbiology; D025065:Borrelia burgdorferi / Q000276:immunology*; D002465:Cell Movement; D006321:Heart / Q000382:microbiology; D006651:Histocytochemistry; D006801:Humans; D007962:Leukocytes / Q000378:metabolism; D008193:Lyme Disease / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009205:Myocarditis / Q000382:microbiology; D010587:Phagocytosis; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D012867:Skin / Q000378:metabolism / Q000382:microbiology; D018709:Statistics, Nonparametric; D015854:Up-Regulation; D001743:Urinary Bladder / Q000378:metabolism / Q000382:microbiology; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism
D055293:Receptors, Urokinase Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator