Interleukin-1β causes excitotoxic neurodegeneration and multiple sclerosis disease progression by activating the apoptotic protein p53

Abstract

Background: Understanding how inflammation causes neuronal damage is of paramount importance in multiple sclerosis (MS) and in other neurodegenerative diseases. Here we addressed the role of the apoptotic cascade in the synaptic abnormalities and neuronal loss caused by the proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor (TNF-α) in brain tissues, and disease progression caused by inflammation in relapsing-remitting MS (RRMS) patients. Results: The effect of IL-1β, but not of TNF-α, on glutamate-mediated excitatory postsynaptic currents was blocked by pifithrin-α (PFT), inhibitor of p53. The protein kinase C (PKC)/transient receptor potential vanilloid 1 (TRPV1) pathway was involved in IL-1β-p53 interaction at glutamatergic synapses, as pharmacological modulation of this inflammation-relevant molecular pathway affected PFT effects on the synaptic action of IL-1β. IL-1β-induced neuronal swelling was also blocked by PFT, and IL-1β increased the expression of p21, a canonical downstream target of activated p53. Consistent with these in vitro results, the Pro/Pro genotype of p53, associated with low efficiency of transcription of p53-regulated genes, abrogated the association between IL-1β cerebrospinal fluid (CSF) levels and disability progression in RRMS patients. The interaction between p53 and CSF IL-1β was also evaluated at the optical coherence tomography (OCT), showing that IL-1β-driven neurodegenerative damage, causing alterations of macular volume and of retinal nerve fibre layer thickness, was modulated by the p53 genotype.

Opposing roles of the triggering receptor expressed on myeloid cells 2 and triggering receptor expressed on myeloid cells-like transcript 2 in microglia activation

“…Microglia secretes cytokines, such as TNF-α and IL-1β, which have both been shown to promote neuronal damage when present in excessive amounts (Monif, et al, 2010, Rossi, et al, 2014). Our results showed that LPS suppressed TREM2 but increased TREML2 mRNA levels, thus promoting microglia to pro-inflammatory status.…”

Inflammasome activation in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE)

“…Congruently, an enhanced striatal neuron EPSC phenotype is correlated with neurodegeneration in EAE (10). CSF from MS patients increases EPSCs, along with signs of neuronal death, in mouse corticostriatal slice cultures; and this effect is mediated by IL-1b (78,79). In the cerebellum, IL-1b increases EPSCs in Purkinje cells during EAE by impairing glutamate clearance by astroglia in neuronal synapses, an effect which is blocked by an IL-1R antagonist (56).…”

An anticomplement agent that homes to the damaged brain and promotes recovery after traumatic brain injury in mice

“…Recent reports showed that sublethal MAC triggers NLRP3 (nucleotidebinding domain, leucine-rich repeat containing family, pyrin domain-containing 3) inflammasome activation and release of IL-1β (24,25). We therefore tested whether MAC regulates secondary inflammatory processes after TBI by inducing inflammasome activation in brain cells, leading to production of IL-1β, which is known to be toxic to neurons (26,27). In situ hybridization demonstrated expression of IL-1β mRNA in injured brains of controls at 72 h post-TBI.…”