TY - JOUR
T1 - The urokinase receptor (uPAR) facilitates clearance of Borrelia burgdorferi
AU - Hovius, J.W.R.
AU - Bijlsma, M.F.
AU - van der Windt, G.J.W.
AU - Wiersinga, W.J.
AU - Boukens, B.J.D.
AU - Coumou, J.
AU - Oei, A.
AU - de Beer, R.
AU - de Vos, A.F.
AU - van 't Veer, C.
AU - van Dam, A.P.
AU - Wang, P.
AU - Fikrig, E.
AU - Levi, M.M.
AU - Roelofs, J.J.T.H.
AU - van der Poll, T.
N1 - With supporting information
PY - 2009/5
Y1 - 2009/5
N2 - 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-1 beta 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.
AB - 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-1 beta 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.
UR - https://pure.uva.nl/ws/files/61979601/ppat.1000447.s001.jpg
UR - https://pure.uva.nl/ws/files/61979603/ppat.1000447.s002.jpg
UR - https://pure.uva.nl/ws/files/61979605/ppat.1000447.s003.zip
UR - https://pure.uva.nl/ws/files/61979607/ppat.1000447.s004.jpg
UR - https://pure.uva.nl/ws/files/61979609/ppat.1000447.s005.jpg
U2 - https://doi.org/10.1371/journal.ppat.1000447
DO - https://doi.org/10.1371/journal.ppat.1000447
M3 - Article
C2 - 19461880
SN - 1553-7366
VL - 5
SP - e1000447
JO - PLoS pathogens
JF - PLoS pathogens
IS - 5
M1 - e1000447
ER -