Glial Cell-Elicited Activation of Brain Microvasculature in Response to Brucella abortus Infection Requires ASC Inflammasome-Dependent IL-1β Production

ANA. M. RODRIGUEZ; MARIA I. FARIAS; ANTONIO C. P. DE OLIVEIRA; M. VICTORIA DELPINO; MIRIAM M. COSTA FRANCO; CARINA C. FERRARI; PAULA BARRIONUEVO; KWANG SIK KIM; GUILLERMO H. GIAMBARTOLOMEI; M. CRUZ MIRAGLIA; PAULA M. Q. BELLOZI; VIDA A. DENNIS, ; FERNANDO PITOSSI; SERGIO C. OLIVEIRA

JOURNAL OF IMMUNOLOGY

AMER ASSOC IMMUNOLOGISTS

Lugar: Bethesda; Año: 2016 vol. 196 p. 3794 - 3805

0022-1767

Blood-brain barrier (BBB) activation and/or alteration are a commonfeature of human neurobrucellosis, but the underlying pathogenic mechanisms are largely unknown. In thismanuscript we described an immune mechanism for inflammatory activation ofhuman brain microvascular endothelial cells (HBMEC) in response to infection withBrucella abortus. Infection of HBMECwith B. abortus induced the secretionof IL-6, IL-8, and MCP-1; and the up-regulation of CD54 (ICAM-1), consistentwith a state of activation. Culturesupernatants (CS) from glial cells (astrocytes and microglia) infected with B. abortus also induced activation of HBMEC. Although B. abortus-infectedglial cells actively secreted IL-1β and TNF-a, activation of HBMEC depended on IL-1β since CS from B. abortus-infected astrocytesand microglia deficient in caspase-1 (CASP-1) and ASC failed to induce activationof HBMEC. Consistently, treatment of CS with neutralizinganti- IL-1β also inhibited HBMEC activation. We also determined that AIM2 andNLRP3 are partially required for CASP-1 activation and IL-1β secretionsuggesting that multiple ASC-dependent inflammasomes contribute to IL-1β-inducedactivation of the brain microvasculature. Inflammasome-mediated IL-1β secretionin glial cells depends on TLR2 and Mal/TIRAP. Finally, neutrophil and monocyte migrationacross HBMEC monolayers was increased by CS from Brucella-infected glial cells in an IL-1β-dependent fashion; and theinfiltration of neutrophils into the brain parenchyma upon intracranialinjection of B. abortus wasinfluenced by NLRP3 and AIM2. Our results indicatethat innate immunity of the CNS sets in motion by B. abortus contributes to the activation of the BBB inneurobrucellosis and IL-1β mediates this phenomenon.