Lack of interleukin-13 receptor α1 delays the loss of dopaminergic neurons during chronic stress

Abstract

BackgroundThe majority of Parkinson’s disease (PD) cases are sporadic and idiopathic suggesting that this neurodegenerative disorder is the result of both environmental and genetic factors. Stress and neuroinflammation are among the factors being investigated for their possible contributions to PD. Experiments in rodents showed that severe chronic stress can reduce the number of dopaminergic neurons in the substantia nigra pars compacta (SNc); the same cells that are lost in PD. These actions are at least in part mediated by increased oxidative stress. Here, we tested the hypothesis that the interleukin-13 receptor alpha 1 (IL-13Rα1), a cytokine receptor whose activation increases the vulnerability of dopaminergic neurons to oxidative damage, participates in the stress-dependent damage of these neurons.MethodsMice were subject to daily sessions of 8 h (acute) stress for 16 weeks (5 days a week), a procedure previously showed to induce loss of dopaminergic neurons in the SNc. The source and the kinetics of interleukin-13 (IL-13), the endogenous ligand of IL-13Rα1, were evaluated 0, 1, 3, 6, and 8 h and at 16 weeks of stress. Identification of IL-13 producing cell-type was performed by immunofluorescent and by in situ hybridization experiments. Markers of oxidative stress, microglia activation, and the number of dopaminergic neurons in IL-13Rα1 knock-out animals (Il13ra1 Y/−) and their wild-type littermates (Il13ra1 Y/+) were evaluated at 16 weeks of stress and at 20 weeks, following a 4 week non-stressed period and compared to non-stressed mice.ResultsIL-13 was expressed in microglial cells within the SN and in a fraction of the tyrosine hydroxylase-positive neurons in the SNc. IL-13 levels were elevated during daily stress and peaked at 6 h. 16 weeks of chronic restraint stress significantly reduced the number of SNc dopaminergic neurons in Il13ra1 Y/+mice. Neuronal loss at 16 weeks was significantly lower in Il13ra1 Y/− mice. However, the loss of dopaminergic neurons measured at 20 weeks, after 4 weeks of non-stress following the 16 weeks of stress, was similar in Il13ra1 Y/+ and Il13ra1 Y/− mice.ConclusionsIL-13, a cytokine previously demonstrated to increase the susceptibility of SNc dopaminergic neurons to oxidative stress, is elevated in the SN by restraint stress. Lack of IL-13Rα1 did not prevent nor halted but delayed neuronal loss in the mouse model of chronic restraint stress. IL-13/IL-13Rα1 may represent a target to reduce the rate of DA neuronal loss that can occur during severe chronic restraint stress.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0862-1) contains supplementary material, which is available to authorized users.

Ethanol Induction of Innate Immune Signals Across BV2 Microglia and SH-SY5Y Neuroblastoma Involves Induction of IL-4 and IL-13

“…Interesting new research also finds that IL-4 and IL-13 may play roles in learning and memory [29,30], suggesting a role for neurons in IL-4 and IL-13 signaling. Furthermore, a novel role for neuronal IL-13Rα1 was recently discovered, in which stimulation of this receptor led to dopaminergic cell loss [28]. In our study, we confirmed that SH-SY5Y IL-4 and IL-13 signaling is enhanced following ethanol treatment in BV2/SH-SY5Y microglial co-cultures, with an increased induction of IL-4R and IL-13R by ethanol in co-cultured SH-SY5Y.…”

“…In brain, microglia appear to express low levels of IL-4 and IL-13 basally but can induce expression under certain conditions [26,27]. Interestingly, IL-13 receptor is located on dopaminergic neurons and overactivation of this receptor has been linked to loss of dopaminergic cells [28], prompting studies on the impact of alcohol exposure due to the importance of dopamine for drug-induced reward. Furthermore, IL-4 and IL-13 also have roles in learning and memory [29,30].…”

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IL13Rα1 protects against rheumatoid arthritis by combating the apoptotic resistance of fibroblast-like synoviocytes

“…Previous study demonstrated that IL13Rα1 regulates the cellular responses to various stressful stimulations that it could promote more fibrosis in response to transforming growth factor-β (TGF-β) [28]. Likewise, neuronal IL13Rα1 increases the susceptibility to oxidative damage [29]. In this study, our loss-and gain-of functional experiments argued IL13Rα1-mediated signaling pathway as a novel molecular program to counter the apoptotic resistance of RA FLSs towards ER stress.…”