Brucella abortus -activated microglia induce neuronal death through primary phagocytosis

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

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 dysfunctionresulting 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 coculturedwith microglia and infected with B. abortus significant neuronal loss occurred. This phenomenonwas dependent on TLR2 activation by Brucella lipoproteins. Neuronal death was not dueto apoptosis, but it was dependent on the microglial release of nitric oxide (NO). B. abortus infectionstimulated 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 neuronalloss by inhibiting microglial phagocytosis without affecting their activation. Taken together, ourresults indicate that B. abortus is not directly toxic to neurons; rather, these cells become distressedand are killed by phagocytosis in the inflammatory surroundings generated by infectedmicroglia. Neuronal loss induced by B. abortus-activated microglia may explain, in part, the neurologicaldeficits observed during neurobrucellosis.