TY - JOUR
T1 - Glial cell-elicited activation of brain microvasculature in response to brucella abortus infection requires asc inflammasome-dependent IL-1b production
AU - Miraglia, M. Cruz
AU - Costa Franco, Miriam M.
AU - Rodriguez, Ana M.
AU - Bellozi, Paula M.Q.
AU - Ferrari, Carina C.
AU - Farias, Maria I.
AU - Dennis, Vida A.
AU - Barrionuevo, Paula
AU - De Oliveira, Antonio C.P.
AU - Pitossi, Fernando
AU - Kim, Kwang Sik
AU - Delpino, M. Victoria
AU - Oliveira, Sergio Costa
AU - Giambartolomei, Guillermo H.
N1 - Funding Information:
This work was supported by Agencia Nacional de Promoción Científica y Tecnológica (Argentina) Grants PICT 2012-2252, 2011-1420, 2011-1501, and 2011-1200, a grant from the Fundación Alberto J. Roemmers (Argentina), Universidad de Buenos Aires Grants UBACYT 20020090200012 and 20020120100128, National Council for Scientific and Technological Development/Brazilian-Argentinian Center for Biotechnology Grant 464711/2014-2, National Council for Scientific and Technological Development Grant 443662/2014-2, Fundaçaõ de Amparo a Pesquisa do estado de Minas Gerais Grant 04003-10, Brazilian Ministry of Education Coordination for the Improvement of Higher Education Personnel Grant 030448/2013-01, and National Science Foundation Centers of Research Excellence in Science and Technology Grant HRD-1241701. M.C.M. is a recipient of a fellowship from the National Scientific and Technical Research Council (Argentina). A.M.R., C.C.F., P.B., F.P., M.V.D., and G.H.G. are members of the Research Career of the National Scientific and Technical Research Council.
PY - 2016/5/1
Y1 - 2016/5/1
N2 - Blood-brain barrier activation and/or dysfunction are a common feature of human neurobrucellosis, but the underlying pathogenic mechanisms are largely unknown. In this article, we describe an immune mechanism for inflammatory activation of human brain microvascular endothelial cells (HBMEC) in response to infection with Brucella abortus. Infection of HBMEC with B. abortus induced the secretion of IL-6, IL-8, and MCP-1, and the upregulation of CD54 (ICAM-1), consistent with a state of activation. Culture supernatants (CS) from glial cells (astrocytes and microglia) infected with B. abortus also induced activation of HBMEC, but to a greater extent. Although B. abortus-infected glial cells secreted IL-1b and TNF-α, activation of HBMEC was dependent on IL-1b because CS from B. abortus-infected astrocytes and microglia deficient in caspase-1 and apoptosis-associated speck-like protein containing a CARD failed to induce HBMEC activation. Consistently, treatment of CS with neutralizing anti-IL-1b inhibited HBMEC activation. Both absent in melanoma 2 and Nod-like receptor containing a pyrin domain 3 are partially required for caspase-1 activation and IL-1b secretion, suggesting that multiple apoptosis-associated speck-like protein containing CARD-dependent inflammasomes contribute to IL-1b-induced activation of the brain microvasculature. Inflammasomemediated IL-1b secretion in glial cells depends on TLR2 and MyD88 adapter-like/TIRAP. Finally, neutrophil and monocyte migration across HBMEC monolayers was increased by CS from Brucella-infected glial cells in an IL-1b-dependent fashion, and the infiltration of neutrophils into the brain parenchyma upon intracranial injection of B. abortus was diminished in the absence of Nod-like receptor containing a pyrin domain 3 and absent in melanoma 2. Our results indicate that innate immunity of the CNS set in motion by B. abortus contributes to the activation of the blood-brain barrier in neurobrucellosis and IL-1b mediates this phenomenon.
AB - Blood-brain barrier activation and/or dysfunction are a common feature of human neurobrucellosis, but the underlying pathogenic mechanisms are largely unknown. In this article, we describe an immune mechanism for inflammatory activation of human brain microvascular endothelial cells (HBMEC) in response to infection with Brucella abortus. Infection of HBMEC with B. abortus induced the secretion of IL-6, IL-8, and MCP-1, and the upregulation of CD54 (ICAM-1), consistent with a state of activation. Culture supernatants (CS) from glial cells (astrocytes and microglia) infected with B. abortus also induced activation of HBMEC, but to a greater extent. Although B. abortus-infected glial cells secreted IL-1b and TNF-α, activation of HBMEC was dependent on IL-1b because CS from B. abortus-infected astrocytes and microglia deficient in caspase-1 and apoptosis-associated speck-like protein containing a CARD failed to induce HBMEC activation. Consistently, treatment of CS with neutralizing anti-IL-1b inhibited HBMEC activation. Both absent in melanoma 2 and Nod-like receptor containing a pyrin domain 3 are partially required for caspase-1 activation and IL-1b secretion, suggesting that multiple apoptosis-associated speck-like protein containing CARD-dependent inflammasomes contribute to IL-1b-induced activation of the brain microvasculature. Inflammasomemediated IL-1b secretion in glial cells depends on TLR2 and MyD88 adapter-like/TIRAP. Finally, neutrophil and monocyte migration across HBMEC monolayers was increased by CS from Brucella-infected glial cells in an IL-1b-dependent fashion, and the infiltration of neutrophils into the brain parenchyma upon intracranial injection of B. abortus was diminished in the absence of Nod-like receptor containing a pyrin domain 3 and absent in melanoma 2. Our results indicate that innate immunity of the CNS set in motion by B. abortus contributes to the activation of the blood-brain barrier in neurobrucellosis and IL-1b mediates this phenomenon.
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U2 - 10.4049/jimmunol.1500908
DO - 10.4049/jimmunol.1500908
M3 - Article
C2 - 26983788
AN - SCOPUS:84974824549
SN - 0022-1767
VL - 196
SP - 3794
EP - 3805
JO - Journal of Immunology
JF - Journal of Immunology
IS - 9
ER -