Anti-inflammatory signals and neurodegeneration

摘要 神经免疫信号调节神经元的功能和存活。我们有强有力的证据表明激活 白介素13受体α1/白介素4受体α(IL-13Rα1/IL-4Rα)复合体的表达 中脑多巴胺(DA)能神经元影响其活性。在大脑中，IL-13Rα1/IL-4Rα唯一表达于 在帕金森病(PD)中丢失的黑质致密部(SNC)神经元。我们还展示了 小胶质细胞和神经元在神经炎症过程中产生的白介素13(IL-13)可以调节 增加多巴胺能细胞的活性，增加其对氧化损伤的敏感性。到目前为止，在以下方面存在差距 了解神经炎症如何导致帕金森病患者DA神经元的选择性丢失。已经确立了 在神经炎症过程中，IL-13Rα1信号的激活可以影响多巴胺能神经元的存活。 在本申请中，我们希望解决这一差距。具体地说，我们希望测试IL-13和 神经元性IL-13Rα1通过刺激一种被称为铁性下垂的受调控的细胞死亡途径而引起损伤。我们也希望 为了确定IL-13和IL-13Rα1在多大程度上促进阿尔茨海默病小鼠模型的神经退行性变。 突触核病(α-SYN)，帕金森病的一个特征，与神经炎症和氧化损伤有关。 这将帮助我们确定靶向IL-13Rα1信号是否可能是减缓 受α-突触核苷酸病(如帕金森病)影响的人类神经变性。FDA的Ruxolitinib的能力- 批准的抑制IL-13Rα1信号转导的药物和新型铁下垂抑制剂CMS121的药物，以降低IL-13R 13-介导的体内损伤也将进行测试。最后，我们建议在一种新的小鼠模型上进行活体实验。 为了验证在早发性帕金森病患者中发现的一种罕见的IL-13基因变体可以 与此突变同源的小鼠的多巴胺能神经元更快地丧失。如果 这些实验的成功将为IL-13和IL-13Rα1是新的假说提供强有力的支持 预防帕金森病或减缓其进展的目标，至少在帕金森病患者的子集中是这样。

Abstract Neuroimmune signals regulate neuronal function and survival. We have strong evidence indicating that activation of the heterodimeric interleukin-13 receptor alpha 1/interleukin-4 receptor alpha (IL-13Rα1/IL-4Rα) complex in midbrain dopaminergic (DA) neurons affects their viability. In the brain, IL-13Rα1/IL-4Rα is uniquely expressed on the neurons of the substantia nigra pars compacta (SNc) that are lost in Parkinson’s disease (PD). We also showed that interleukin 13 (IL-13), produced during neuroinflammation by microglia and neurons, can modulate the activity of dopaminergic cells and increase their susceptibility to oxidative damage. To date, there is a gap in understanding how neuroinflammation contributes to the selective loss of DA neurons in PD. Having established that activation of IL-13Rα1 signaling can affect the survival of dopaminergic neurons during neuroinflammation, in the present application we wish to address this gap. Specifically, we wish to test the hypothesis that IL-13 and neuronal IL-13Rα1 cause damage by stimulating a regulated cell death pathway called ferroptosis. We also wish to determine to what extent IL-13 and IL-13Rα1 contribute to neurodegeneration in a mouse model of alpha- synucleinopathy (α-Syn), a hallmark trait of PD that is associated with neuroinflammation and oxidative damage. This will help us determine whether targeting IL-13Rα1 signaling might be a viable approach to slow neurodegeneration in humans affected by α-synucleinopathy such as PD. The ability of ruxolitinib, an FDA- approved drug that inhibits IL-13Rα1 signaling and that of the novel ferroptosis inhibitor CMS121, to reduce IL- 13-mediated damage in vivo will also be tested. Finally, we propose in vivo experiments un a novel mouse model to test the hypothesis that a rare genetic variant of IL-13 found in individuals diagnosed with early-onset PD can contribute to more rapid loss of dopaminergic neurons in a mouse with the homologue of this mutation. If successful, these experiments will provide strong support for the hypothesis that IL-13 and IL-13Rα1 are novel targets for preventing PD or slowing its progression, at least in a sub-set of PD patients.