Abstract
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-1β 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.
Highlights
Lyme borreliosis, an emerging tick-borne disease in both the New and Old world, is caused by spirochetes belonging to the Borrelia burgdorferi sensu lato group and is predominantly transmitted by Ixodes ticks [1]
We describe the function of uPA Receptor (uPAR) in the immune response against the spirochete; using uPAR knock-out mice, we show that uPAR plays an important role in phagocytosis of B. burgdorferi by leukocytes both in vitro as well as in vivo
We show that the mechanism by which uPAR is involved in the phagocytosis of B. burgdorferi is independent of ligation to its natural ligand urokinase Plasminogen Activator (uPA) or uPAR’s role in fibrinolysis
Summary
An emerging tick-borne disease in both the New and Old world, is caused by spirochetes belonging to the Borrelia burgdorferi sensu lato group and is predominantly transmitted by Ixodes ticks [1]. Besides functioning as a proteinase receptor, uPAR affects leukocyte migration and adhesion [15,16,17,18,19,20], as well as phagocytosis [19,21], through intracellular signaling. This occurs, in part, independently of ligation of uPA by uPAR [22,23]
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