Brucella abortus induces TNF-a-dependent astroglial MMP-9 secretion through mitogen-activated protein kinases.

MIRAGLIA M.C.; DELPINO M.V.; SCIAN R.; GARCÍA SAMARTINO C.; BARRIONUEVO P.; IBAÑEZ A.; CORIA M.L.; VELÁSQUEZ L.N.; CASSATARO J.; GIAMBARTOLOMEI G.H.

Buenos Aires

Congreso; Brucellosis 2011, International Research Conference - 64th Brucellosis Research Conference.; 2011

Asociacion Argentina de Microbiologia (AAM)

Central nervous system (CNS) invasion by bacteria of the genus Brucella results in an inflammatory disorder called neurobrucellosis. We have recently demonstrated that B. abortus infects microglia and astrocytes eliciting the production of a variety of pro-inflammatory cytokines which contribute to CNS damage. Matrix metalloproteinases (MMP) have been implicated in inflammatory tissue destruction in a range of pathological situation in the CNS. MMP are able to catabolyze all components of the extracellular matrix, thus possessing unlimited potential to damage CNS tissues. Indeed, increased MMP secretion is induced by pro-inflammatory cytokines in a variety of CNS diseases characterized by tissue destructive pathology.  In this study, we investigated the cytokine network that regulate MMP secretion from Brucella-infected astrocytes and examined the mitogen-activated protein kinases (MAPK) signaling pathways involved. B. abortus infection induced the secretion of MMP-9 from murine astrocytes in a dose-dependent fashion. The phenomenon was independent of bacterial viability and was recapitulated by L-Omp19, a B. abortus lipoprotein model, but not its LPS. B. abortus and L-Omp19 readily activated p38 and Erk1/2 MAPK, thus enlisting these pathways among the kinase pathways that the bacterium may address as they invade astrocytes. Inhibition of both p38 and Erk1/2 significantly diminished MMP-9 secretion, and totally abrogated production of this MMP when both MAPK pathways were inhibited simultaneously. A concomitant abrogation of B. abortus- and L-Omp19-induced TNF-a production was observed when p38 and Erk1/2 pathways were inhibited, indicating that TNF-a could be implicated in MMP9 secretion. MMP9 secretion induced by B. abortus or L-Omp19 was completely abrogated when experiments were conducted in the presence of a TNF-a blocking antibody while an isotype control had no effect. Also, B. abortus or L-Omp19 were unable to induce MMP-9 secretion from astrocytes of TNFRp55 KO mice. In contrast MMP-9 was secreted when astrocytes were obtained from wild type C57BL/6 mice. Our results indicate that the inflammatory response elicited by B. abortus in astrocytes would lead to the production of MMP and that MAPK may play a role in both phenomena. MAPK inhibition thus may be considered as a strategy to control inflammation and SNC damage in neurobrucellosis.