Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu 211166, PR China.
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu 211166, PR China.
Brain Behav Immun. 2021 Jul;95:310-320. doi: 10.1016/j.bbi.2021.04.003. Epub 2021 Apr 8.
Complement pathway over-activation has been implicated in a variety of neurological diseases. However, the signaling pathways governing astrocytic complement activation in Parkinson's disease (PD) are poorly understood. Kir6.1, a pore-forming subunit of ATP-sensitive potassium (K-ATP) channel, is prominently expressed in astrocytes and exhibits anti-inflammatory effects. Therefore, we hypothesize that Kir6.1/K-ATP channel may regulate astrocytic complement activation in the pathogenesis of PD. In this study, astrocytic Kir6.1 knockout (KO) mice were used to examine the effect of astrocytic Kir6.1/K-ATP channel on astrocytic complement activation triggered by the lipopolysaccharide (LPS). Here, we found that astrocytic Kir6.1 KO mice showed more dopaminergic neuron loss and more astrocyte reactivity in substantia nigra compacta than controls. We also found that astrocytic Kir6.1 KO increased the expression of complement C3 in astrocytes in LPS-induced mouse model of PD. Mechanistically, astrocytic Kir6.1 KO promoted astroglial NF-κB activation to elicit extracellular release of C3, which in turn interacted with neuronal C3aR to induce neuron death. Blocking complement function by NF-κB inhibitor or C3aR antagonist rescued the aggravated neuron death induced by Kir6.1 KO. Collectively, our findings reveal that astrocytic Kir6.1/K-ATP channel prevents neurodegeneration in PD via astrocyte-neuron cross talk through NF-κB/C3/C3aR signaling and suggest that targeting astroglial Kir6.1/K-ATP channel-NF-κB-C3-neuronal C3aR signaling represents a novel therapeutic strategy for PD.
补体途径过度激活与多种神经退行性疾病有关。然而，帕金森病（PD）中星形胶质细胞补体激活的信号通路仍知之甚少。Kir6.1 是 ATP 敏感性钾 (K-ATP) 通道的孔形成亚基，在星形胶质细胞中表达丰富，并具有抗炎作用。因此，我们假设 Kir6.1/K-ATP 通道可能调节 PD 发病机制中的星形胶质细胞补体激活。在这项研究中，使用星形胶质细胞 Kir6.1 敲除（KO）小鼠来检查星形胶质细胞 Kir6.1/K-ATP 通道对脂多糖（LPS）触发的星形胶质细胞补体激活的影响。在这里，我们发现星形胶质细胞 Kir6.1 KO 小鼠比对照小鼠在黑质致密部显示出更多的多巴胺能神经元丢失和更多的星形胶质细胞反应性。我们还发现，星形胶质细胞 Kir6.1 KO 增加了 LPS 诱导的 PD 小鼠模型中星形胶质细胞中补体 C3 的表达。在机制上，星形胶质细胞 Kir6.1 KO 促进星形胶质细胞 NF-κB 激活，引发 C3 的细胞外释放，进而与神经元 C3aR 相互作用诱导神经元死亡。NF-κB 抑制剂或 C3aR 拮抗剂阻断补体功能可挽救 Kir6.1 KO 引起的神经元死亡加剧。总之，我们的研究结果表明，星形胶质细胞 Kir6.1/K-ATP 通道通过星形胶质细胞-神经元相互作用，通过 NF-κB/C3/C3aR 信号通路防止 PD 中的神经退行性变，并表明靶向星形胶质细胞 Kir6.1/K-ATP 通道-NF-κB-C3-神经元 C3aR 信号通路代表了一种新的 PD 治疗策略。
