Brucella abortus-infected macrophages modulate T lymphocytes to promote osteoclastogenesis via IL-17.
The pathogenic mechanisms of bone loss caused by Brucella species have not been completely deciphered. Although T lymphocytes (LTs) are considered important to control infection, the mechanism of Brucella-induced T-cell responses to immunopathological features is not known. We present in vitro and in vivo evidence showing that Brucella abortus-induced inflammatory response leads to the activation of LTs, which further promote osteoclastogenesis. Pre-activated murine LTs treated with culture supernatant from macrophages infected with B. abortus induced bone marrow-derived monocytes (BMMs) to undergo osteoclastogenesis. Furthermore, osteoclastogenesis was mediated by CD4(+) T cells. Although B. abortus-activated T cells actively secreted the pro-osteoclastogenic cytokines RANKL and IL-17, osteoclastogenesis depended on IL-17, because osteoclast generation induced by Brucella-activated T cells was completely abrogated when these cells were cultured with BMMs from IL-17 receptor knockout mice. Neutralization experiments indicated that IL-6, generated by Brucella infection, induced the production of pro-osteoclastogenic IL-17 from LTs. By using BMMs from tumor necrosis factor receptor p55 knockout mice, we also demonstrated that IL-17 indirectly induced osteoclastogenesis through the induction of tumor necrosis factor-α from osteoclast precursors. Finally, extensive and widespread osteoclastogenesis was observed in the knee joints of mice injected with Brucella-activated T cells. Our results indicate that activated T cells, elicited by B. abortus-infected macrophages and influenced by the inflammatory milieu, promote the generation of osteoclasts, leading to bone loss.
Institute for the Study of Humoral Immunity, Faculty of Pharmacy and Biochemistry, University of Buenos Aires, Argentina.
Guillermo H
GH
Giambartolomei
Romina
R
Scian
Eva
E
Acosta-Rodríguez
Carlos A
CA
Fossati
M Victoria
MV
Delpino
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D002003:Brucella abortus / Q000276:immunology*; D002006:Brucellosis / Q000276:immunology / Q000382:microbiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D020381:Interleukin-17 / Q000096:biosynthesis / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010010:Osteoclasts / Q000276:immunology* / Q000378:metabolism; D010012:Osteogenesis / Q000276:immunology*; D053245:RANK Ligand / Q000378:metabolism; D053722:Receptors, Interleukin-17 / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D013977:Tibia / Q000276:immunology / Q000473:pathology; D053319:Tumor Necrosis Factor Decoy Receptors / Q000172:deficiency / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D020381:Interleukin-17; D015850:Interleukin-6; D053245:RANK Ligand; D053722:Receptors, Interleukin-17; D047888:Receptors, Tumor Necrosis Factor, Type I; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; C069521:recombinant human tumor necrosis factor-binding protein-1