Brucella abortus-activated microglia induce neuronal death through primary phagocytosis

ANA MARIA RODRIGUEZ; M. VICTORIA DELPINO; M. CRUZ MIRAGLIA; MIRIAM M. COSTA FRANCO; PAULA BARRIONUEVO; VIDA DENNIS; SERGIO C. OLIVEIRA; GUILLERMO H. GIAMBARTOLOMEI

GLIA

WILEY-LISS, DIV JOHN WILEY & SONS INC

Lugar: New York; Año: 2017

0894-1491

Inflammation has long been implicated as a contributor to pathogenesis in neurobrucellosis. Manyof the associated neurocognitive symptoms of neurobrucellosis may be the result of neuronal dysfunction resulting from the inflammatory response induced by Brucella abortus infection in thecentral nervous system. In this manuscript, we describe an immune mechanism for inflammatoryactivation of microglia that leads to neuronal death upon B. abortus infection. B. abortus wasunable to infect or harm primary cultures of mouse neurons. However, when neurons were cocultured 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. NOsecreted 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.