Type I interferons (IFNs), including IFN-α and IFN-β, are immunomodulatory cytokines that can act in the brain to induce either anti- or pro-inflammatory effects. For instance, IFN-β is known to produce beneficial effects in multiple sclerosis, but also to cause several neuropsychiatric side-effects, including depression and cognitive deficits. Moreover, both IFN-α and IFN-β have been shown to be involved in neurodegenerative processes in humans and animals. An important aspect of central IFN action is the interaction with neurotrophins, which are master regulators of neurogenesis, survival and differentiation of neuronal and non-neuronal cells. Although IFNs have been shown to affect neurotrophin synthesis and release in various cell types, relatively little is known on their effects on expression and functional activity of the Trk neurotrophin receptors. We have previously reported that in primary neurons and differentiated SH-SY5Y neuroblastoma cells long-term exposure to type I IFNs induces a down-regulation of the TrkB receptor and impairs the neurotrophic activity of BDNF, which is known to sustain synaptic plasticity, cognitive functions and mood control. Conversely, type I IFNs cause up-regulation of the p75NTR/TrkA receptor complex, which is associated with enhanced NGF signaling and attenuation of IFN-β pro-apoptotic effects. Here, we show that IFN-β also alters the expression and signaling of the TrkC receptor, which mediates the neurotrophic activity of NT3. We found that in differentiated SH-SY5Y cells prolonged exposure to IFN-β inhibits NT3-induced activation of different signaling pathways, including PI3K/Akt, PLCγ1 and ERK1/2, and impairs NT3 anti-apoptotic activity. These effects are associated with an enhanced expression of the truncated TrkC-T1 isoform. TrkC-T1 knockdown in IFN-β-treated cells potentiates TrkC pro-survival signaling and restores NT3 ability to inhibit IFN-β-induced apoptosis. These data indicate that IFN-β can impair NT3/TrkC function through a novel mechanisms involving the up-regulation of TrkC-T1, which acts as a dominant-negative receptor of TrkC.
Differential modulation of neurotrophin receptor expression and signaling by Type I Interferons
DEDONI, SIMONA;OLIANAS, MARIA CONCETTA;INGIANNI, ANGELA;ONALI, PIER LUIGI
2015-01-01
Abstract
Type I interferons (IFNs), including IFN-α and IFN-β, are immunomodulatory cytokines that can act in the brain to induce either anti- or pro-inflammatory effects. For instance, IFN-β is known to produce beneficial effects in multiple sclerosis, but also to cause several neuropsychiatric side-effects, including depression and cognitive deficits. Moreover, both IFN-α and IFN-β have been shown to be involved in neurodegenerative processes in humans and animals. An important aspect of central IFN action is the interaction with neurotrophins, which are master regulators of neurogenesis, survival and differentiation of neuronal and non-neuronal cells. Although IFNs have been shown to affect neurotrophin synthesis and release in various cell types, relatively little is known on their effects on expression and functional activity of the Trk neurotrophin receptors. We have previously reported that in primary neurons and differentiated SH-SY5Y neuroblastoma cells long-term exposure to type I IFNs induces a down-regulation of the TrkB receptor and impairs the neurotrophic activity of BDNF, which is known to sustain synaptic plasticity, cognitive functions and mood control. Conversely, type I IFNs cause up-regulation of the p75NTR/TrkA receptor complex, which is associated with enhanced NGF signaling and attenuation of IFN-β pro-apoptotic effects. Here, we show that IFN-β also alters the expression and signaling of the TrkC receptor, which mediates the neurotrophic activity of NT3. We found that in differentiated SH-SY5Y cells prolonged exposure to IFN-β inhibits NT3-induced activation of different signaling pathways, including PI3K/Akt, PLCγ1 and ERK1/2, and impairs NT3 anti-apoptotic activity. These effects are associated with an enhanced expression of the truncated TrkC-T1 isoform. TrkC-T1 knockdown in IFN-β-treated cells potentiates TrkC pro-survival signaling and restores NT3 ability to inhibit IFN-β-induced apoptosis. These data indicate that IFN-β can impair NT3/TrkC function through a novel mechanisms involving the up-regulation of TrkC-T1, which acts as a dominant-negative receptor of TrkC.
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