Role of the IL-13 system in dopaminergic cell death

描述(申请人提供)：我们假设抗炎细胞因子IL-13和IL-4在黑质致密部(SNC)多巴胺能神经元的死亡中发挥重要作用，这些细胞与人类帕金森病(PD)中丢失的细胞相同。这一假说是基于我们对小鼠的初步研究，该研究表明，白介素13受体α1链(IL-13Ralpha1)在黑质中的DA神经元中高表达，并且该受体缺陷的小鼠可以防止在低剂量LPS慢性外周注射期间发生的多巴胺(DA)神经元的丧失。此外，使用多巴胺能细胞系进行的体外研究表明，尽管IL-13单独对DA神经元没有有害影响，但它强烈增强了温和氧化应激的毒性。另一种能够激活IL-13Ralpha1信号的细胞因子IL-4也得到了类似的结果。综上所述，这些结果提示了一种新的机制，即抗炎细胞因子可以在应激条件下导致神经元丢失。我们建议从三个具体目标来研究我们的假设。在SA1中，我们将在体外确定IL-13(和IL-4)信号与氧化应激之间的相互作用如何诱导神经元损伤。在SA2中，我们将在神经炎症模型中研究这些细胞因子在体内神经元丢失中的作用。在SA3中，我们将确定炎症过程中IL-13和IL-4的细胞来源。这些研究与了解炎症在帕金森病发病机制中的作用高度相关，并可能确定治疗该疾病的新靶点。

DESCRIPTION (provided by applicant): We hypothesize that the anti-inflammatory cytokines IL-13 and IL-4 play an important role in the death of dopaminergic neurons in the Substantia nigra pars compacta (SNc), the same cells that are lost in human Parkinson's disease (PD). This hypothesis is based on our preliminary studies in mice which showed that interleukin 13 receptor alpha 1 chain (IL-13Ralpha1), is highly expressed in DA neurons in the SNc and that mice that are deficient is this receptor are protected from the loss of dopaminergic (DA) neurons that occurs during chronic peripheral injection with low doses of LPS. Furthermore, in vitro studies using a dopaminergic cell line showed that while IL-13 alone does not have harmful effects on DA neurons, it strongly potentiates the toxicity of mild oxidative stress. Similar resuls were obtained with IL-4, another cytokine capable of activating IL- 13Ralpha1-dependent signaling. Together these results suggest a novel mechanism whereby anti-inflammatory cytokines can contribute to neuronal loss under conditions of stress. We propose to investigate our hypothesis in three specific aims. In SA1, we will determine how the interaction between IL-13 (and IL-4) signaling and oxidative stress induces neuronal damage in vitro. In SA2, we will investigate the contribution of each of these cytokines to neuronal loss in vivo in a model of neuro-inflammation. In SA3, we will determine the cellular source of IL-13 and IL-4 during inflammation. These studies are highly relevant to understanding the role of inflammation in the pathogenesis of PD and may identify novel therapeutic targets for the treatment of this disease.