CD14 cooperates with complement receptor 3 to mediate MyD88-independent phagocytosis of Borrelia burgdorferi.
Phagocytosis of Borrelia burgdorferi, the causative agent of Lyme disease, is a poorly understood process, despite its importance during the host immune response to infection. B. burgdorferi has been shown to bind to different receptors on the surface of phagocytic cells, including the β(2) integrin, complement receptor 3 (CR3). However, whether these receptors mediate the phagocytosis of the spirochete remains unknown. We now demonstrate that CR3 mediates the phagocytosis of the spirochete by murine macrophages and human monocytes. Interaction of B. burgdorferi with the integrin is not sufficient, however, to internalize the spirochete; phagocytosis requires the interaction of CR3 with the GPI-anchored protein, CD14, independently of TLR/MyD88-induced or inside-out signals. Interestingly, the absence of CR3 leads to marked increases in the production of TNF in vitro and in vivo, despite reduced spirochetal uptake. Furthermore, the absence of CR3 during infection with B. burgdorferi results in the inefficient control of bacterial burdens in the heart and increased Lyme carditis. Overall, our data identify CR3 as a MyD88-independent phagocytic receptor for B. burgdorferi that also participates in the modulation of the proinflammatory output of macrophages. These data also establish a unique mechanism of CR3-mediated phagocytosis that requires the direct cooperation of GPI-anchored proteins.
Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, MA 01003, USA.
Kelly L
KL
Hawley
Chris M
CM
Olson
Juan M
JM
Iglesias-Pedraz
Nicolás
N
Navasa
Jorge L
JL
Cervantes
Melissa J
MJ
Caimano
Hooman
H
Izadi
Robin R
RR
Ingalls
Utpal
U
Pal
Juan C
JC
Salazar
Justin D
JD
Radolf
Juan
J
Anguita
D000818:Animals; D025065:Borrelia burgdorferi / Q000276:immunology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000276:immunology*; D008193:Lyme Disease / Q000276:immunology*; D016177:Macrophage-1 Antigen / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology; D010587:Phagocytosis / Q000276:immunology*; D016133:Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018950:Lipopolysaccharide Receptors; D016177:Macrophage-1 Antigen; D014409:Tumor Necrosis Factor-alpha