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Fig. 8 | Journal of Neuroinflammation

Fig. 8

From: Fundamentally different roles of neuronal TNF receptors in CNS pathology: TNFR1 and IKKβ promote microglial responses and tissue injury in demyelination while TNFR2 protects against excitotoxicity in mice

Fig. 8

Schematic representation of the different roles of neuronal TNFR in CNS pathology described in the present study. (A) Neuronal TNFR1 and IKKβ promote neuroinflammation, demyelination, and axonal damage in the context of demyelination (1) signaled by EAE or CPZ toxicity. solTNF present in the microenvironment of the inflammatory lesion (2) engages TNFR1 present on the surface of neurons (as well as other cell types) and, either directly through a neuronal stress response (3), or indirectly by increasing OLG damage, enhances microglia responses and further promotes solTNF secretion and inflammation (4). (B) Neuronal TNFR2 is necessary for preconditioning neuroprotection against glutamate excitotoxicity. Preconditioning of neurons by challenge with low-dose KA (in vivo, 1a), preincubation with solTNF (in vitro, 1b), or preincubation with a TNFR2 agonist (in vitro, 1c) protects them against subsequent glutamate excitotoxicity (2) induced by high dose KA (in vivo) or NMDA (in vitro). In vitro experiments using TNF and TNFR mutant cells revealed that astrocytes can mediate the preconditioning effect of solTNF, via TNFR1 and expression of tmTNF, which in turn is necessary for interaction with neuronal TNFR2 (3) and the induction of neuroprotection mechanisms (4). Ligation of neuronal TNFR2 by the TNFR2 agonist (1c) is sufficient to reproduce this effect in vitro

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