title: Macrophage-elicited osteoclastogenesis in response to Brucella abortus infection requires TLR2/MyD88-dependent TNF-α production.
abstract: Osteoarticular complications are common in human brucellosis, but the pathogenic mechanisms involved are largely unknown. In this manuscript, we described an immune mechanism for inflammatory bone loss in response to infection by Brucella abortus. We established a requirement for MyD88 and TLR2 in TNF-α-elicited osteoclastogenesis in response to B. abortus infection. CS from macrophages infected with B. abortus induced BMM to undergo osteoclastogenesis. Although B. abortus-infected macrophages actively secreted IL-1β, IL-6, and TNF-α, osteoclastogenesis depended on TNF-α, as CS from B. abortus-infected macrophages failed to induce osteoclastogenesis in BMM from TNFRp55⁻/⁻ mice. CS from B. abortus-stimulated MyD88⁻/⁻ and TLR2⁻/⁻ macrophages failed to express TNF-α, and these CS induced no osteoclast formation compared with that of the WT or TLR4⁻/⁻ macrophages. Omp19, a B. abortus lipoprotein model, recapitulated the cytokine production and subsequent osteoclastogenesis induced by the whole bacterium. All phenomena were corroborated using human monocytes, indicating that this mechanism could play a role in human osteoarticular brucellosis. Our results indicate that B. abortus, through its lipoproteins, may be involved in bone resorption through the pathological induction of osteoclastogenesis.
authors.affiliation: Instituto de Estudios de la Inmunidad Humoral (CONICET), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: M Victoria
authors.initials: MV
authors.lastname: Delpino
authors.forename: Paula
authors.initials: P
authors.lastname: Barrionuevo
authors.forename: Gilson Costa
authors.initials: GC
authors.lastname: Macedo
authors.forename: Sergio Costa
authors.initials: SC
authors.lastname: Oliveira
authors.forename: Silvia Di
authors.initials: SD
authors.lastname: Genaro
authors.forename: Romina
authors.initials: R
authors.lastname: Scian
authors.forename: M Cruz
authors.initials: MC
authors.lastname: Miraglia
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Fossati
authors.forename: Pablo C
authors.initials: PC
authors.lastname: Baldi
authors.forename: Guillermo H
authors.initials: GH
authors.lastname: Giambartolomei
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000494:pharmacology; D001425:Bacterial Outer Membrane Proteins / Q000494:pharmacology; D002003:Brucella abortus / Q000502:physiology*; D002006:Brucellosis / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects / Q000502:physiology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D006801:Humans; D008074:Lipoproteins / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects / Q000502:physiology; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D010010:Osteoclasts / Q000502:physiology*; D053245:RANK Ligand / Q000096:biosynthesis; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000172:deficiency; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000502:physiology*
chemical_list: D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; D017077:Culture Media, Conditioned; D016207:Cytokines; D008074:Lipoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C097319:OMP19 protein, Brucella abortus; D053245:RANK Ligand; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; C505689:Tnfsf11 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha