Brucella abortus-infected macrophages modulate T lymphocytes to promote osteoclastogenesis via IL-17.

GIAMBARTOLOMEI GH; SCIAN R; ACOSTA RODRIGUEZ EV; FOSSATI CA; DELPINO MV

AMERICAN JOURNAL OF PATHOLOGY

AMER SOC INVESTIGATIVE PATHOLOGY, INC

Año: 2012 p. 887 - 896

0002-9440

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 proosteoclastogenic 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 proosteoclastogenic 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- 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.