Fundamentally Different Roles of Neuronal TNF Receptors in CNS Pathology: TNFR1 and IKKβ Promote Microglial Responses and Tissue Injury in Demyelination, TNFR2 Protects in Excitotoxicity in Mice (original) (raw)

2021, Research Square (Research Square)

BACKGROUND During in ammatory demyelination TNF receptor 1 (TNFR1) mediates detrimental proin ammatory effects of soluble TNF, whereas TNFR2 mediates bene cial effects of transmembrane TNF through oligodendrocytes, microglia, and possibly other cell types. This model supports use of selective inhibitors of soluble TNF/TNFR1 as antin ammatory drugs for CNS disease. A potential obstacle is the neuroprotective effect of soluble TNF pretreatment described in cultured neurons, but the in vivo relevance is unknown. METHODS To address this question we generated mice with neuron-speci c depletion of TNFR1, TNFR2 or IKKβ and applied experimental models of in ammatory demyelination and acute and preconditioning glutamate excitotoxicity. We also investigated the molecular and cellular requirements of soluble TNF (and therefore TNFR1) neuroprotection by generating astrocyte-neuron co-cultures with different combinations of wildtype and TNF and TNF receptor knockout cells and measuring NMDA excitotoxicity in vitro. RESULTS Neither neuronal TNFR1 nor TNFR2 protected mice during in ammatory demyelination. In fact, both neuronal TNFR1 and neuronal IKKβ promoted microglial responses and tissue injury, and TNFR1 was further required for oligodendrocyte loss and axonal damage in cuprizone demyelination. In contrast, neuronal TNFR2 increased preconditioning protection in a kainic acid excitotoxicity model in mice, and limited hippocampal neuron death. The neuroprotective effects of neuronal TNFR2 observed in vivo were further investigated in vitro. Here as expected, pretreatment of astrocyte-neuron co-cultures with soluble TNF protected them against NMDA excitotoxicity. However, protection was dependent on astrocyte, not neuronal TNFR1, on astrocyte transmembrane TNF-neuronal TNFR2 interactions, and was reproduced by a TNFR2 agonist. CONCLUSIONS These results demonstrate that neuronal TNF receptors perform fundamentally different roles in CNS pathology in vivo, with neuronal TNFR1 and IKKβ promoting microglial in ammation and neurotoxicity in demyelination, and neuronal TNFR2 mediating neuroprotection in excitotoxicity. They also reveal that previously-described neuroprotective effects of soluble TNF (and therefore TNFR1) against glutamate excitotoxicity in vitro are indirect, and mediated by astrocyte transmembrane TNF-neuron TNFR2 interactions. These results consolidate the concept that selective inhibition of soluble TNF/TNFR1 with maintenance of TNFR2 function would have anti-in ammatory and neuroprotective properties required for the safe treatment of CNS disease.