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

Abstract: A classic proinflammatory T helper cell type 1 (TH1) response directed against intracellu-lar 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 in-fection by the extracellular pathogen Borrelia burgdorferi, we tested the hypothesis that os-teopontin may be required to induce TH1 re-sponses 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 suscep-tible to B. burgdorferi-induced arthritis as litter-mate controls. Furthermore, equal numbers of spi-rochetes, as measured by quantitative polymerase chain reaction of the B. burgdorferi gene recA in spp1/ and B6129F3 wild-type littermates, sug-gested that susceptibility to infection was not de-pendent on this cytokine. Neither of the B6129F3 parental mouse strains lacked the ability to secrete osteopontin. spp1/mice and controls had immu-noglobulin G2 titers, suggestive of a TH1 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 intracel-lular pathogens was circumvented by the ability of the extracellular pathogen B. burgdorferi to induce macrophages directly to produce proinflammatory cytokines. J. Leukoc. Biol. 77: 000–000; 2005