Astrocyte conversion to proinflammatory-neurodegenerative phenotype is a key step in evolution of traumatic brain injury

CIERI B; MAILING I; VILLARREAL A; MURTA V; RAMOS AJ

Congreso; Reunion Anual de la Sociedad Argentina de Investigacion en Neurociencias 2018; 2019

Reactive gliosis characterizes astroglial response to brain injury. The mechanisms that propagate reactive astrogliosis and facilitate neurodegeneration are not fully understood. It has been proposed that core-derived DAMP have a major role in the reactive astrogliosis propagation and neurodegeneration. However, in silico modeling has shown that DAMP release does not justify the experimental findings (Auzmendi et al.,Mol. Neurobiol 2019). Using a model of traumatic brain injury (TBI) by stab wound in C57BL/6 mice and reconstituted glial cultures from TLR2KO mice, we here aimed to understand the role of TLR2 and downstream NFkB activation in reactive gliosis and neurodegeneration. Animal motor deficits were analyzed by computer-assisted open field. Our results showed that TBI induces reactive gliosis that propagates from the injury to distal brain, with a maximal reactivity at 7 days post TBI (DPI). This time point also showed significant neurodegeneration and neurological deficit. NFkB blockage with 150 mg/kg sulfasalazine reduced reactive gliosis without showing neurological improvement; while TLR2KO mice presented increased reactive gliosis but better performance on open field at 7DPI. In vitro reactive gliosis is exacerbated in TLR2KO astrocytes cocultured with wild type microglia. We conclude that reactive gliosis does not necessarily parallel with neurological outcome, being the proinflammatory-neurodegenerative polarization a key step in the evolution of the TBI.