Abstract
Excitotoxicity is a major component of neurodegenerative diseases and is typically accompanied by an inflammatory response. Cytokines IL-1alpha and IL-1beta are key regulators of this inflammatory response and modulate the activity of numerous cell types, including neurons. IL-1RAcPb is an isoform of IL-1RAcP expressed specifically in neurons and promotes their survival during acute inflammation. Here, we investigated in vivo whether IL-1RAcPb also promotes neuronal survival in a model of excitotoxicity. Intrastriatal injection of kainic acid (KA) in mice caused a strong induction of IL-1 cytokines mRNA in the brain. The stress response of cortical neurons at 12 h post-injection, as measured by expression of Atf3, FoxO3a, and Bdnf mRNAs, was similar in WT and AcPb-deficient mice. Importantly however, a delayed upregulation in the transcription of calpastatin was significantly higher in WT than in AcPb-deficient mice. Finally, although absence of AcPb signaling had no effect on damage to neurons in the cortex at early time points, it significantly impaired their long-term survival. These data suggest that in a context of excitotoxicity, stimulation of IL-1RAcPb signaling may promote the activity of a key neuroprotective mechanism.
Highlights
Neuronal dysfunctions and damage associated with excitotoxic insults are intrinsically linked with aberrant calcium signaling in neurons and are implicated in a wide variety of neurodegenerative diseases, including strokes, epilepsy and Alzheimer’s disease
As a large body of evidence suggests that kainic acid (KA)-induced excitotoxicity is accompanied by an increase in the expression of numerous pro-inflammatory cytokines, we sought to confirm that cytokines IL-1α and IL-1β are de novo synthesized
Expression for either cytokines remained undetectable in mice injected with vehicle. These data confirm that an intrastriatal injection of KA causes a strong induction of IL-1α and IL-1β cytokines in the brain, albeit with different kinetics
Summary
Neuronal dysfunctions and damage associated with excitotoxic insults are intrinsically linked with aberrant calcium signaling in neurons and are implicated in a wide variety of neurodegenerative diseases, including strokes, epilepsy and Alzheimer’s disease. Binding of either cytokines to the IL-1 receptor type 1 (IL-1R1) causes its heterodimerization with IL-1 receptor accessory protein (IL-1RAcP, or AcP) (Korherr et al, 1997; Cullinan et al, 1998). This complex recruits adaptor protein MyD88, which allows for the activation of signaling pathways that regulate the activity of MAP kinases and NF-κB transcription factors (Muzio et al, 1997; Medzhitov et al, 1998). With respect to excitotoxic insults, IL-1 signaling appears to increase neuronal dysfunctions and death
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