TNF Alpha and Fas Mediate Tissue Damage and Functional Outcome after Traumatic Brain Injury in Mice

Abstract

Tumor necrosis factor-alpha (TNFα) and Fas are induced after traumatic brain injury (TBI); however, their functional roles are incompletely understood. Using controlled cortical impact (CCI) and mice deficient in TNFα, Fas, or both (TNFα/Fas—/—), we hypothesized that TNFα and Fas receptor mediate secondary TBI in a redundant manner. Compared with wild type (WT), TNFα/Fas—/— mice had improved motor performance from 1 to 4 days ( P < 0.05), improved spatial memory acquisition at 8 to 14 days ( P < 0.05), and decreased brain lesion size at 2 and 6 weeks after CCI ( P < 0.05). Protection in TNFα/Fas—/— mice from histopathological and motor deficits was reversed by reconstitution with recombinant TNFα before CCI, and TNFα—/— mice administered anti-Fas ligand antibodies had improved spatial memory acquisition versus similarly treated WT mice ( P < 0.05). Tumor necrosis factor-alpha/Fas—/— mice had decreased the numbers of cortical cells with plasmalemma damage at 6h ( P < 0.05 versus WT), and reduced matrix metalloproteinase-9 activity in injured brain at 48 and 72 h after CCI. In immature mice subjected to CCI, genetic inhibition of TNFα and Fas conferred beneficial effects on histopathology and spatial memory acquisition in adulthood (both P < 0.05 versus WT), suggesting that the beneficial effects of TNFα/Fas inhibition may be permanent. The data suggest that redundant signaling pathways initiated by TNFα and Fas play pivotal roles in the pathogenesis of TBI, and that biochemical mechanisms downstream of TNFα/Fas may be novel therapeutic targets to limit neurological sequelae in children and adults with severe TBI.