NLRP3 Inflammasome Is Expressed and Functional in Mouse Brain Microglia but Not in Astrocytes

Neuroinflammation is the local reaction of the brain to infection, trauma, toxic molecules or protein aggregates. The brain resident macrophages, microglia, are able to trigger an appropriate response involving secretion of cytokines and chemokines, resulting in the activation of astrocytes and recruitment of peripheral immune cells. IL-1β plays an important role in this response; yet its production and mode of action in the brain are not fully understood and its precise implication in neurodegenerative diseases needs further characterization. Our results indicate that the capacity to form a functional NLRP3 inflammasome and secretion of IL-1β is limited to the microglial compartment in the mouse brain. We were not able to observe IL-1β secretion from astrocytes, nor do they express all NLRP3 inflammasome components. Microglia were able to produce IL-1β in response to different classical inflammasome activators, such as ATP, Nigericin or Alum. Similarly, microglia secreted IL-18 and IL-1α, two other inflammasome-linked pro-inflammatory factors. Cell stimulation with α-synuclein, a neurodegenerative disease-related peptide, did not result in the release of active IL-1β by microglia, despite a weak pro-inflammatory effect. Amyloid-β peptides were able to activate the NLRP3 inflammasome in microglia and IL-1β secretion occurred in a P2X7 receptor-independent manner. Thus microglia-dependent inflammasome activation can play an important role in the brain and especially in neuroinflammatory conditions.神经炎症（Neuroinflammation）是大脑针对感染、创伤、毒性分子或蛋白质聚集物产生的局部应答反应。大脑常驻巨噬细胞——小胶质细胞（microglia）——能够触发恰当的应答程序，包括分泌细胞因子与趋化因子，进而激活星形胶质细胞并招募外周免疫细胞。白细胞介素-1β（IL-1β）在该应答过程中发挥关键作用；然而其在大脑中的产生机制与作用方式尚未完全阐明，且它在神经退行性疾病中的具体参与程度仍需进一步表征。本研究结果显示，小鼠大脑内仅小胶质细胞区室具备形成功能性NLRP3炎性小体（NLRP3 inflammasome）并分泌IL-1β的能力。我们未观察到星形胶质细胞分泌IL-1β的现象，且星形胶质细胞也不表达全部NLRP3炎性小体组分。小胶质细胞可响应多种经典炎性小体激活剂（如三磷酸腺苷（ATP）、尼日利亚菌素（Nigericin）或明矾（Alum））产生IL-1β。同样，小胶质细胞还可分泌另外两种与炎性小体相关的促炎因子：白细胞介素-18（IL-18）与白细胞介素-1α（IL-1α）。尽管α-突触核蛋白（α-synuclein，一种与神经退行性疾病相关的肽类物质）对小胶质细胞具有较弱的促炎效应，但其刺激并未导致小胶质细胞释放有活性的IL-1β。β淀粉样蛋白（Amyloid-β）能够激活小胶质细胞中的NLRP3炎性小体，且IL-1β的分泌以不依赖P2X7受体（P2X7 receptor）的方式进行。综上，依赖小胶质细胞的炎性小体激活在大脑中，尤其是神经炎症状态下，可发挥重要作用。