Department of Neurobiology and Second Affiliated Hospital, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, China.
Molecular Neuropharmacology Laboratory and State Key Laboratory of Optometry, Ophthalmology and Vision Science, School of Optometry and Ophthalmology, Wenzhou, Zhejiang, China.
Brain. 2019 Mar 1;142(3):700-718. doi: 10.1093/brain/awy351.
Ectonucleotidase-mediated ATP catabolism provides a powerful mechanism to control the levels of extracellular adenosine. While increased adenosine A2A receptor (A2AR) signaling has been well-documented in both Parkinson's disease models and patients, the source of this enhanced adenosine signalling remains unclear. Here, we show that the ecto-5'-nucleotidase (CD73)-mediated adenosine formation provides an important input to activate A2AR, and upregulated CD73 and A2AR in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease models coordinatively contribute to the elevated adenosine signalling. Importantly, we demonstrate that CD73-derived adenosine-A2AR signalling modulates microglial immunoresponses and morphological dynamics. CD73 inactivation significantly attenuated lipopolysaccharide-induced pro-inflammatory responses in microglia, but enhanced microglia process extension, movement and morphological transformation in the laser injury and acute MPTP-induced Parkinson's disease models. Limiting CD73-derived adenosine substantially suppressed microglia-mediated neuroinflammation and improved the viability of dopaminergic neurons and motor behaviours in Parkinson's disease models. Moreover, CD73 inactivation suppressed A2AR induction and A2AR-mediated pro-inflammatory responses, whereas replenishment of adenosine analogues restored these effects, suggesting that CD73 produces a self-regulating feed-forward adenosine formation to activate A2AR and promote neuroinflammation. We further provide the first evidence that A2A enhanced inflammation by antagonizing dopamine-mediated anti-inflammation, suggesting that the homeostatic balance between adenosine and dopamine signalling is key to microglia immunoresponses. Our study thus reveals a novel role for CD73-mediated nucleotide metabolism in regulating neuroinflammation and provides the proof-of-principle that targeting nucleotide metabolic pathways to limit adenosine production and neuroinflammation in Parkinson's disease might be a promising therapeutic strategy.
外核苷酸酶介导的 ATP 分解代谢为控制细胞外腺苷水平提供了一种强大的机制。虽然在帕金森病模型和患者中都有大量证据表明腺苷 A2A 受体 (A2AR) 的信号增强，但这种增强的腺苷信号的来源仍不清楚。在这里，我们表明，外核苷酸酶 (CD73) 介导的腺苷形成提供了一个重要的输入来激活 A2AR，并且在 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 诱导的帕金森病模型中上调的 CD73 和 A2AR 协同促进了升高的腺苷信号。重要的是，我们证明 CD73 衍生的腺苷-A2AR 信号调节小胶质细胞免疫反应和形态动力学。CD73 失活显著减弱了小胶质细胞中脂多糖诱导的促炎反应，但增强了激光损伤和急性 MPTP 诱导的帕金森病模型中小胶质细胞突起的延伸、运动和形态转化。限制 CD73 衍生的腺苷显著抑制小胶质细胞介导的神经炎症，并改善帕金森病模型中多巴胺能神经元的活力和运动行为。此外，CD73 失活抑制了 A2AR 的诱导和 A2AR 介导的促炎反应，而腺苷类似物的补充恢复了这些效应，表明 CD73 产生了一种自我调节的正向腺苷形成来激活 A2AR 并促进神经炎症。我们进一步提供了第一个证据表明 A2A 通过拮抗多巴胺介导的抗炎作用增强炎症，表明腺苷和多巴胺信号之间的动态平衡是小胶质细胞免疫反应的关键。我们的研究因此揭示了 CD73 介导的核苷酸代谢在调节神经炎症中的新作用，并提供了靶向核苷酸代谢途径以限制帕金森病中腺苷产生和神经炎症的原理性证据，这可能是一种有前途的治疗策略。
