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Published online before print February 4, 2005

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(Journal of Leukocyte Biology. 2005;77:710-718.)
© 2005 by Society for Leukocyte Biology

Borrelia burgdorferi, an extracellular pathogen, circumvents osteopontin in inducing an inflammatory cytokine response

Kathleen Craig-Mylius^*,1, Georg F. Weber^,2, Jenifer Coburn and Lisa Glickstein^*,3

^* Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Charlestown;
Molecular Oncology Research Institute and
Division of Geographic Medicine and Infectious Diseases, Tufts-New England Medical Center, Boston, Massachusetts

³ Correspondence: Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, 149 13th Street, Room 8301, Charlestown, MA, 02129. E-mail: lglickstein{at}partners.org

A classic proinflammatory T helper cell type 1 (T_H1) response directed against intracellular pathogens includes the cytokine osteopontin, which acts predominantly on macrophages, where it induces the secretion of interleukin (IL)-12 and suppresses the secretion of IL-10. As cell-mediated immune responses play an important role in the resistance to Lyme arthritis, a manifestation of infection by the extracellular pathogen Borrelia burgdorferi, we tested the hypothesis that osteopontin may be required to induce T_H1 responses and inflammation. The role of osteopontin was tested in vivo and using ex vivo macrophages in B6129F3 mice susceptible to experimental Lyme arthritis. Mice of this genetic background and those fully backcrossed to C57BL/6, which lacked osteopontin expression (spp1^–/–), were as susceptible to B. burgdorferi-induced arthritis as littermate controls. Furthermore, equal numbers of spirochetes, as measured by quantitative polymerase chain reaction of the B. burgdorferi gene recA in spp1^–/– and B6129F3 wild-type littermates, suggested that susceptibility to infection was not dependent on this cytokine. Neither of the B6129F3 parental mouse strains lacked the ability to secrete osteopontin. spp1^–/– mice and controls had immunoglobulin G₂ titers, suggestive of a T_H1 response. B. burgdorferi was able to directly stimulate the secretion of the proinflammatory cytokines IL-12 and tumor necrosis factor from wild-type and spp1^–/– macrophages alike. These results indicate that the usually critical role of osteopontin in the induction of cellular immune responses to intracellular pathogens was circumvented by the ability of the extracellular pathogen B. burgdorferi to induce macrophages directly to produce proinflammatory cytokines.

Key Words: mouse • macrophage • IL-12 • TNF-

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