期刊
GLIA
卷 65, 期 7, 页码 1137-1151出版社
WILEY
DOI: 10.1002/glia.23149
关键词
microglia activation; neurobrucellosis; neuroinflammation; neurotoxicity
资金
- Agencia Nacional de Promocion Cientifica y Tecnologica (ANPCYT-Argentina) [PICT 2011-1200, 2011-1420, 2011-1501, 2012-2252, 2014-1111, 2014-2162, 2014-1925]
- Fundacion Alberto J. Roemmers (Argentina)
- Universidad de Buenos Aires [UBACYT 20020090200012, 20020120100128]
- CNPq/CBAB [464711/2014-2]
- CNPq [443662/2014-2]
- FAPEMIG [0083715]
- CAPES [030448/2013-01]
- NSFCREST [HRD-1241701]
Inflammation has long been implicated as a contributor to pathogenesis in neurobrucellosis. Many of the associated neurocognitive symptoms of neurobrucellosis may be the result of neuronal dysfunction resulting from the inflammatory response induced by Brucella abortus infection in the central nervous system. In this manuscript, we describe an immune mechanism for inflammatory activation of microglia that leads to neuronal death upon B. abortus infection. B. abortus was unable to infect or harm primary cultures of mouse neurons. However, when neurons were co-cultured with microglia and infected with B. abortus significant neuronal loss occurred. This phenomenon was dependent on TLR2 activation by Brucella lipoproteins. Neuronal death was not due to apoptosis, but it was dependent on the microglial release of nitric oxide (NO). B. abortus infection stimulated microglial proliferation, phagocytic activity and engulfment of neurons. NO secreted by B. abortus-activated microglia induced neuronal exposure of the eat-me signal phosphatidylserine (PS). Blocking of PS-binding to protein milk fat globule epidermal growth factor-8 (MFG-E8) or microglial vitronectin receptor-MFG-E8 interaction was sufficient to prevent neuronal loss by inhibiting microglial phagocytosis without affecting their activation. Taken together, our results indicate that B. abortus is not directly toxic to neurons; rather, these cells become distressed and are killed by phagocytosis in the inflammatory surroundings generated by infected microglia. Neuronal loss induced by B. abortus-activated microglia may explain, in part, the neurological deficits observed during neurobrucellosis.
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