Tumor necrosis factor α is reparative via TNFR1 in the hippocampus and via TNFR2 in the striatum after virus-induced encephalitis

Differentiating between injurious and reparative factors facilitates appropriate therapeutic intervention. We evaluated the role of tumor necrosis factor α (TNFα) in parenchymal brain pathology resolution following virus-induced encephalitis from a picornavirus, Theiler's murine encephalomyelitis virus (TMEV). We infected the following animals with TMEV for 7 to 270 days: B6/129 TNF^-/- mice (without TNFα expression), B6/129 TNFR1^-/- mice (without TNFα receptor 1 expression), and B6/129 TNFR2^-/- mice (without TNFα receptor 2 expression). Normal TNFα-expressing controls were TMEV-infected B6, 129/J, B6/129F1 and B6/129F2 mice. Whereas all strains developed inflammation and neuronal injury in the hippocampus and striatum 7 to 21 days postinfection (dpi), the control mice resolved the pathology by 45 to 90 dpi. However, parenchymal hippocampal and striatal injury persisted in B6/129 TNF^-/- mice following infection. Treating virus-infected mice with active recombinant mouse TNFα resulted in less hippocampal and striatal pathology, whereas TNFα-neutralizing treatment worsened pathology. T1 "black holes" appeared on MRI during early infection in the hippocampus and striatum in all mice but persisted only in TNF^-/- mice. TNFR1 mediated hippocampal pathology resolution whereas TNFR2 mediated striatal healing. These findings indicate the role of TNFα in resolution of sublethal hippocampal and striatal injury.