CD73-derived adenosine controls inflammation and neurodegeneration by modulating dopamine signalling
CD73-derived adenosine controls inflammation and neurodegeneration by modulating dopamine signalling
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CD73 衍生的腺苷通过调节多巴胺信号传导来控制炎症和神经退行性变
DOI：
10.1093/brain/awy351
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发表时间：
2019-03-01
期刊：
影响因子：
14.5
通讯作者：
Gao, Zhihua
中科院分区：
文献类型：
--
作者：
Meng, Fan;Guo, Zhige;Gao, Zhihua
外核苷酸酶介导的ATP催化剂提供了一种强大的机制来控制细胞外腺苷的水平。虽然增加的腺苷A（2A）受体（A（2A）R）信号传导在帕金森病模型和患者中都有很好的记录，但这种增强的腺苷信号传导的来源仍不清楚。在这里，我们表明，外-5'-核苷酸酶（CD73）介导的腺苷形成提供了一个重要的输入激活A（2A）R，和上调的CD73和A（2A）R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协调有助于腺苷信号的升高。重要的是，我们证明，CD73衍生的腺苷-A（2A）R信号调节小胶质细胞的免疫反应和形态动力学。CD73失活显著减弱了脂多糖诱导的小胶质细胞促炎反应，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的突起延伸、运动和形态转化。在帕金森病模型中，限制CD73衍生的腺苷实质上抑制了小胶质细胞介导的神经炎症，并改善了多巴胺能神经元的活力和运动行为。此外，CD73失活抑制A（2A）R诱导和A（2A）R介导的促炎反应，而补充腺苷类似物恢复了这些作用，表明CD73产生自我调节前馈腺苷形成以激活A（2A）R并促进神经炎症。我们进一步提供了第一个证据表明，A（2A）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稳态平衡是小胶质细胞免疫应答的关键。因此，我们的研究揭示了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可能是一种有前途的治疗策略的原理证明。
Ectonucleotidase-mediated ATP catabolism provides a powerful mechanism to control the levels of extracellular adenosine. While increased adenosine A(2A) receptor (A(2A)R) 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 A(2A)R, and upregulated CD73 and A(2A)R 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-A(2A)R 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 A(2A)R induction and A(2A)R-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 A(2A)R and promote neuroinflammation. We further provide the first evidence that A(2A) 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.