PDF(Pubmed)
Abstract：
The immune system has a dynamic role in neurodegenerative diseases, and purinergic receptors allow immune cells to recognize neuronal signaling, cell injury, or stress. Purinergic Receptor 7 (P2RX7) can modulate inflammatory cascades and its expression is upregulated in Alzheimer\'s disease (AD) brain tissue. P2RX7 expression is enriched in microglia, and elevated levels are found in microglia surrounding amyloid-beta plaques in the brain. While P2RX7 is thought to play a role in neurodegenerative diseases, how it modulates pathology and disease progression is not well understood. Here, we utilize a human monocyte-derived microglia-like cell (MDMi) model to interrogate P2RX7 activation and downstream consequences on microglia function. By using MDMi derived from human donors, we can examine how human donor variation impacts microglia function. We assessed P2RX7-driven IL1β and IL18 production and amyloid-beta peptide 1-42 (Aβ1-42) uptake levels. Our results show that ATP-stimulation of MDMi triggers upregulation of IL1β and IL18 expression. This upregulation of cytokine gene expression is blocked with the A740003 P2RX7 antagonist. We find that high extracellular ATP conditions also reduced MDMi capacity for Aβ1-42 uptake, and this loss of function is prevented through A740003 inhibition of P2RX7. In addition, pretreatment of MDMi with IL-1RA limited ATP-driven IL1β and IL18 gene expression upregulation, indicating that ATP immunomodulation of P2RX7 is IL-1R dependent. Aβ1-42 uptake was higher with IL-1RA pretreatment compared to ATP treatment alone, suggesting P2RX7 regulates phagocytic engulfment through IL-1 signaling. Overall, our results demonstrate that P2RX7 is a key response protein for high extracellular ATP in human microglia-like cells, and its function can be modulated by IL-1 signaling. This work opens the door to future studies examining anti-IL-1 biologics to increase the clearance of amyloid-beta.
摘要：
免疫系统在神经退行性疾病中具有动态作用，嘌呤受体允许免疫细胞识别神经元信号，细胞损伤,或压力。嘌呤能受体7(P2RX7)可调节炎症级联反应,其在阿尔茨海默病(AD)脑组织中的表达上调。P2RX7表达富集在小胶质细胞中，在大脑中β淀粉样蛋白斑块周围的小胶质细胞中发现水平升高。虽然P2RX7被认为在神经退行性疾病中起作用，它如何调节病理和疾病进展还没有很好的理解。这里,我们利用人类单核细胞衍生的小胶质细胞样细胞(MDMi)模型来询问P2RX7活化和下游对小胶质细胞功能的影响.通过使用来自人类捐赠者的MDMi，我们可以研究人类供体变异如何影响小胶质细胞功能。我们评估了P2RX7驱动的IL1β和IL18的产生以及淀粉样β肽1-42（Aβ1-42）的摄取水平。我们的结果表明，ATP刺激MDMi引发IL1β和IL18表达上调。细胞因子基因表达的这种上调被A740003P2RX7拮抗剂阻断。我们发现，高细胞外ATP条件也降低了Aβ1-42摄取的MDMi能力，并且通过A740003抑制P2RX7来防止这种功能丧失。此外,用IL-1RA限制ATP驱动的IL1β和IL18基因表达上调预处理MDMi，表明P2RX7的ATP免疫调节是IL-1R依赖性的。与单独的ATP治疗相比，IL-1RA预处理的Aβ1-42摄取更高，提示P2RX7通过IL-1信号调节吞噬。总的来说,我们的结果表明，P2RX7是人类小胶质细胞样细胞中高细胞外ATP的关键反应蛋白，其功能可通过IL-1信号调节。这项工作为将来研究抗IL-1生物制剂以增加淀粉样β的清除打开了大门。
