Abstract
Interleukin-1 (IL-1), a proinflammatory cytokine synthesized and released by activated microglia, can cause dopaminergic neurodegeneration leading to Parkinson’s disease (PD). However, it is uncertain whether IL-1 can act directly, or by exacerbating the harmful actions of other brain insults. To ascertain the role of the IL-1 pathway on dopaminergic neurodegeneration and motor skills during aging, we compared mice with impaired [caspase-1 knockout (casp1−/−)] or overactivated IL-1 activity [IL-1 receptor antagonist knockout (IL-1ra−/−)] to wild-type (wt) mice at young and middle age. Their motor skills were evaluated by the open-field and rotarod tests, and quantification of their dopamine neurons and activated microglia within the substantia nigra were performed by immunohistochemistry. IL-1ra−/− mice showed an age-related decline in motor skills, a reduced number of dopamine neurons, and an increase in activated microglia when compared to wt or casp1−/− mice. Casp1−/− mice had similar changes in motor skills and dopamine neurons, but fewer activated microglia cells than wt mice. Our results suggest that the overactivated IL-1 pathway occurring in IL-1ra−/− mice in the absence of inflammatory interventions (e.g., intracerebral injections performed in animal models of PD) increased activated microglia, decreased the number of dopaminergic neurons, and reduced their motor skills. Decreased IL-1 activity in casp1−/− mice did not yield clear protective effects when compared with wt mice. In summary, in the absence of overt brain insults, chronic activation of the IL-1 pathway may promote pathological aspects of PD per se, but its impairment does not appear to yield advantages over wt mice.
Highlights
A growing body of evidence suggests that inflammatory mediators play a pivotal role in aging and neurodegenerative disorders such as Parkinson’s disease (PD), a condition that affect more than 1 % of the population aged 60 years and older in industrialized countries [1]
We have ascertained the role of the IL-1 pathway on long-term locomotion and motor coordination in wt, IL-1 receptor antagonist (IL-1ra)−/−, and casp1−/− mice displaying normal, overactive, or impaired IL1 pathway, respectively
Our results in IL1ra−/− mice suggest that overactivation of microglia cells by IL-1 decreases the number of dopaminergic neurons, which in turn reduces locomotion and motor coordination to promote pathological aspects of parkinsonism
Summary
A growing body of evidence suggests that inflammatory mediators play a pivotal role in aging and neurodegenerative disorders such as Parkinson’s disease (PD), a condition that affect more than 1 % of the population aged 60 years and older in industrialized countries [1]. Activation of microglia, either by age or different insults, has been proposed as a key neuroinflammatory process leading to the progression of dopaminergic neurodegeneration [3]. The IL-1 system involves two essential agonists, IL-1 alpha (IL1α) and IL-1 beta (IL-1β), as well as the endogenous antagonist, IL-1 receptor antagonist (IL-1ra) [7] Both IL-1α/β exert similar biological effects by binding to IL-1 receptor 1 (IL1R1), whereas IL-1ra blocks IL-1α/β biological activity by competing with them by binding to IL-1R1 [7, 8]. Upon binding to IL-1R1, IL-1ra does not trigger any second messenger signal [7, 8] Another key component of the IL-1 system is caspase-1 (casp1), a cysteine protease that, when cleaved, activates the immature form of IL-1. IL1ra and casp are two key targets that modulate the IL-1 system
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