Parkinson’s disease (PD) and related synucleinopathies are characterized by chronic neuroinflammation leading to the premise that anti-inflammatory therapies could ameliorate synucleinopathy and associated sequelae. To test this idea, we used recombinant adeno-associated viruses (AAV) to express the anti-inflammatory cytokine, Interleukin (Il)-10, in Line M83 transgenic mice that expresses the PD-associated A53T mutant human α-synuclein (αSyn). Contrary to our expectations, we observed that intraspinal Il-10 expression initiated at birth upregulated microgliosis and led to early death in homozygous M83+/+ mice. We further observed that Il-10 preconditioning led to reduced lifespan in the hemizygous M83+/− mice injected with preformed αSyn aggregates in hindlimb muscles. To determine the mechanistic basis for these adverse effects, we took advantage of the I87A variant Il-10 (vIl-10) that has predominantly immunosuppressive properties. Sustained intraspinal expression of vIl-10 in preformed αSyn-aggregate seeded M83+/− mice resulted in earlier death, accelerated αSyn pathology, pronounced microgliosis, and increased apoptosis compared to control mice. AAV-vIl-10 expression robustly induced p62 and neuronal LC3B accumulation in these mice, indicating that Il-10 signaling mediated preconditioning of the neuraxis can potentially exacerbate αSyn accumulation through autophagy dysfunction in the neurons. Together, our data demonstrate unexpected adverse effects of both Il-10 and its immunosuppressive variant, vIl-10, in a mouse model of PD, highlighting the pleiotropic functions of immune mediators and their complex role in non-cell autonomous signaling in neurodegenerative proteinopathies.

帕金森氏病 (PD) 和相关的突触核蛋白病的特征是慢性神经炎症，导致抗炎疗法可以改善突触核蛋白病和相关后遗症的前提。为了验证这个想法，我们使用重组腺相关病毒 (AAV) 在表达 PD 相关 A53T 突变体人 α-突触核蛋白 (αSyn) 的 M83 系转基因小鼠中表达抗炎细胞因子白细胞介素 (Il)-10 . 与我们的预期相反，我们观察到在出生时启动的脊髓内 Il-10 表达上调了小胶质细胞增生并导致纯合 M83+/+ 小鼠的早期死亡。我们进一步观察到 Il-10 预处理导致在后肢肌肉中注射预制 αSyn 聚集体的半合子 M83+/− 小鼠的寿命缩短。为了确定这些不利影响的机制基础，我们利用了主要具有免疫抑制特性的 I87A 变体 Il-10 (vIl-10)。与对照小鼠相比，在预先形成的 αSyn 聚集体接种的 M83+/- 小鼠中，vIl-10 的持续脊柱内表达导致更早的死亡、加速的 αSyn 病理学、显着的小胶质细胞增生和细胞凋亡增加。AAV-vIl-10 表达在这些小鼠中强烈诱导 p62 和神经元 LC3B 积累，表明 Il-10 信号介导的神经轴预处理可能通过神经元中的自噬功能障碍加剧 αSyn 积累。总之，我们的数据证明了 Il-10 及其免疫抑制变体 vIl-10 在 PD 小鼠模型中的意外副作用，