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

MIRAGLIA M. C., COSTA FRANCO M. M., RODRÍGUEZ A. M., BARRIONUEVO P, KIM K. S., DELPINO M. V., OLIVEIRA S. C., GIAMBARTOLOMEI G. H.

Congreso; LXIII Reunión Anual de la Sociedad Argentina de Inmunología; 2015

Blood-brain barrier (BBB) activation and/or dysfunction are a commonfeature of human neurobrucellosis, but the underlying pathogenic mechanisms are largely unknown. In thismanuscript we describe an immune mechanism for inflammatory activation of humanbrain microvascular endothelial cells (HBMEC) in response to infection with Brucella 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; but to a greater extent. Although B. abortus-infectedglial cells secreted IL-1β and TNF-a, activation of HBMEC depended on IL-1β since CS from B. abortus-infectedastrocytes and microglia deficient in caspase-1 (CASP-1) and ASC failed toinduce HBMEC activation. Consistently, treatment of CS with neutralizinganti-IL-1β inhibited HBMEC activation. Both AIM2 and NLRP3 are partiallyrequired for CASP-1 activation and IL-1β secretion suggesting that multipleASC-dependent inflammasomes contribute to IL-1β-induced activation of the brainmicrovasculature. Inflammasome-mediated IL-1β secretion in glial cells dependson TLR2 and Mal/TIRAP. Finally, neutrophil and monocyte migration across HBMEC monolayers wasincreased by CS from Brucella-infectedglial cells in an IL-1β-dependent fashion; and the infiltration of neutrophils into the brain parenchyma uponintracranial injection of B. abortuswas diminished in the absence of NLRP3 and AIM2. Our results indicate that innate immunity of the CNS set in motion by B. abortus contributes to theactivation of the BBB in neurobrucellosis and IL-1β mediates this phenomenon.