Poly(I:C) promotes TNFa/TNFR1-dependent oligodendrocyte death in mixed glial cultures

Steelman, Andrew J; Li, Jianrong

Likewise, not all studies have assigned a detrimental role to TNFα in the CNS. For example, while injection of recombinant TNFα into the optic nerve resulted in demyelination [49] , repeated intracerebral injection of TNFα resulted in hemorrhage, reactive gliosis and infiltration of mononuclear and polymorphonuclear cells but appeared to have no cytolytic effects [50] . Moreover, in the cuprizone model of toxic demyelination, which is characterized by extensive reactive gliosis, TNFα -/mice exhibit delayed demyelination but also impaired remyelination [36] . In addition, it has recently been shown that the resolution of pathology following virus-induced encephalitis requires TNFα for repair in the striatum and the hippocampus through TNFR1 and TNFR2 respectively [51] . On the other hand, Theiler's murine encephalomyelitis virus infection of TNFR1 -/were found to exhibit up to 80% fewer seizures during virusinduced encephalitis when compared to control mice [52] . Ambiguous effects of TNFα have also been demonstrated in multiple sclerosis. Elevated TNFα levels in the cerebral spinal fluid of MS patients precede exacerbation and correlate with disease progression [39] . TNFα immunoreactivity has been localized to astrocytes on the lesion edge but not in the lesion center of MS patients [37] . Furthermore, increased expression of TNFR1 and TNFR2 in oligodendrocytes at the edge of chronic active lesions was reported [53, 54] . While these findings suggest an involvement for TNFα in the pathogenesis of MS, treatment with monoclonal neutralizing anti-TNFα antibodies as well as neutralizing soluble receptors has, paradoxically, resulted in MS disease exacerbation [55, 56] . Even more alarming, anti-TNFα therapy in rheumatoid arthritis patients has been associated with the onset of monophasic demyelination including optic neuritis that subsided after treatment withdrawal [57] [58] [59] [60] and with the onset of MS [57, 61] . As the capacity for TNFα therapy to neutralize CNS TNFα was not directly examined, these data may imply that peripheral TNFα is somehow required for maintaining demyelinating disease quiescence. Although the underlying mechanism remains unknown the recent finding that increased susceptibility to MS is associated with a single nucleotide polymorphism within the sixth intron of the tnfr1 gene calls upon further investigation as to the role the TNFα/TNFR1 pathway in this disease [62, 63] .