Role of the IL-1 Pathway in Dopaminergic Neurodegeneration and Decreased Voluntary Movement

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.

Inflammasome Activation by Methamphetamine Potentiates Lipopolysaccharide Stimulation of IL-1β Production in Microglia

“…Currently, we have no direct evidence to conclude the Meth-potentiated neurotoxicity is solely mediated by the over-released mature form of IL-1β in supernatants. As IL-1β, on the one hand, has been shown to be neurotoxic by others (Ye et al, 2013; Brough et al, 2015; Stojakovic et al, 2017), and the released active IL-1β in response to Meth-induced inflammasome activation, on the other hand, may also have a positive feedback on microglial inflammatory responses, which could promote the release of IL-1β and/or other neurotoxic factors and confound the neurotoxic effects observed in this study.…”

Transcriptomic approach predicts a major role for transforming growth factor beta type 1 pathway in L‐Dopa‐induced dyskinesia in parkinsonian rats

“…Migration of immune cells into the brain or immune cell activation during chronic L‐Dopa treatment may contribute to the upregulated inflammatory mediators 66 . A role of TNFα and IL‐1β cytokines in PD pathology has been reported in recent studies 67‐69 . Data of early exposure to anti‐TNFα therapy in patients with inflammatory bowel disease showed substantially reduced PD incidence 67 .…”

“…Furthermore, administration of TNFα specific inhibitor, XPro1595 to hemiparkinsonian rats reduced nigral cell loss and glial activation, indicating a mechanistic improvement of PD pathology 68 . Activation of IL‐1 pathway has been associated with dopamine loss and parkinsonism during aging, and reduction of IL‐1 activity may have neuroprotective effects 69 . Conceivably, these inflammatory mediators could play a role in modulating adaptive changes during chronic L‐Dopa treatment.…”

Pseudane-VII Regulates LPS-Induced Neuroinflammation in Brain Microglia Cells through the Inhibition of iNOS Expression

“…Many studies have suggested that microglia-mediated proinflammatory mediators, such as IL-1β, IL-6, and TNF-α, were recognized to contribute to neurodegeneration [20]. The overproduction of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α in the brain can result in tissue damage and nerve cell death.…”