Glial cell-elicited activation of brain microvasculature in response to Brucella abortus infection requires ASC inflammasome-dependent IL-1beta production.

MIRAGLIA, M. CRUZ; SILVA COSTA FRANCO, MIRIAM M.; RODRIGUEZ, ANA MARÍA; BARRIONUEVO, PAULA; KWANG S. KIM; DELPINO, M. VICTORIA; OLIVEIRA, SERGIO C.; GIAMBARTOLOMEI, GUILLERMO H.

Buenos Aires

Congreso; LXIII Reunión Anual de la Sociedad Argentina de Inmunología. II Meeting Franco Argentino de Inmunología. IV Reunión de la Sociedad Latinoamericana de Inmunodeficiencias.; 2015

Sociedad Argentina de Inmunología (SAI)

Blood-brain barrier activation is a common feature of human neurobrucellosis, but the underlying mechanisms are largely unknown. Recently, we have demonstrated that the activation of brain microvascular endothelial cells (HBMEC) by glial cells is mediated by Brucella-induced IL-1beta through the activation of ASC and CASP-1. Since ASC is essential for the CASP-1 response to B. abortus in glial cells, a NLR should be involved in IL-1beta production and the subsequent activation of HBMEC. To address whether NLRP3 and AIM2 are important for IL-1beta secretion during infection of glial cells and activation of HBMEC, astrocytes and microglia from C57BL/6, NLRP3 and AIM2 KO mice were infected with B. abortus. HBMEC stimulation with culture supernatants (CS) from B. abortus-infected glial cells from WT mice induced the secretion of IL-6, IL-8 and MCP-1 and the up-regulation of ICAM-1, while activation of HBMEC was abolished when these cells were stimulated with CS from B. abortus-infected glial cells from NLRP3 and AIM2 KO mice (p 0.001 vs. WT). Transmigration of neutrophils and monocytes in an in vitro model of brain endothelium was also evaluated. Cellular transmigration occurred when the monolayer was stimulated with CS from WT glial cells, but it was not observed when HBMEC were stimulated with CS from NLRP3 and AIM2 KO cells (p 0.01 vs. WT). Experiments to ascertain whether inflammasome-dependent IL-1beta production influences migration of cells into the brain parenchyma are under investigation. These results demonstrate that ASC inflammasomes are critical for the glial activation of HBMEC by B. abortus.