Chronic, sustained inflammation underlies many pathological conditions, including neurodegenerative diseases. Divalent manganese (Mn2+) exposure can stimulate neurotoxicity by increasing inflammation. In this study, we examined whether Mn2+ activates the multiprotein NLRP3 inflammasome complex to promote neuroinflammation. Exposing activated mouse microglial cells to Mn2+ substantially augmented NLRP3 abundance, caspase-1 cleavage, and maturation of the inflammatory cytokine interleukin-1β (IL-1β). Exposure of mice to Mn2+ had similar effects in brain microglial cells. Furthermore, Mn2+ impaired mitochondrial ATP generation, basal respiratory rate, and spare capacity in microglial cells. These data suggest that Mn-induced mitochondrial defects drove the inflammasome signal amplification. We found that Mn induced cell-to-cell transfer of the inflammasome adaptor protein ASC in exosomes. Furthermore, primed microglial cells exposed to exosomes from Mn-treated mice released more IL-1β than did cells exposed to exosomes from control-treated animals. We also observed that welders exposed to manganese-containing fumes had plasma exosomes that contained more ASC than did those from a matched control group. Together, these results suggest that the divalent metal manganese acts as a key amplifier of NLRP3 inflammasome signaling and exosomal ASC release.

中文翻译：

---

锰可激活NLRP3炎性体信号传导，并在小胶质细胞中传播ASC的外体释放。

慢性持续性炎症是许多病理状况的基础，包括神经退行性疾病。暴露于二价锰（Mn2 +）可通过增加炎症来刺激神经毒性。在这项研究中，我们检查了Mn2 +是否激活多蛋白NLRP3炎症小体复合物以促进神经炎症。将活化的小鼠小神经胶质细胞暴露于Mn2 +会大大增加NLRP3的丰度，caspase-1的裂解以及炎性细胞因子白介素1β（IL-1β）的成熟。小鼠暴露于Mn2 +对脑小胶质细胞具有相似的作用。此外，Mn2 +会损害线粒体ATP的生成，基础呼吸频率和小胶质细胞的备用能力。这些数据表明锰诱导的线粒体缺陷驱动了炎性体信号放大。我们发现锰诱导了外泌体中炎性体衔接蛋白ASC的细胞间转移。此外，暴露于来自Mn处理小鼠的外泌体的致敏小胶质细胞释放的IL-1β比暴露于来自对照治疗动物的外泌体的细胞释放的IL-1β多。我们还观察到，暴露于含锰烟气的焊工的血浆外泌体比匹配对照组的血浆外泌体含有更多的ASC。在一起，这些结果表明，二价金属锰充当NLRP3炎性体信号传导和外泌体ASC释放的关键放大器。我们还观察到，暴露于含锰烟气的焊工的血浆外泌体比匹配对照组的血浆外泌体含有更多的ASC。在一起，这些结果表明，二价金属锰充当NLRP3炎性体信号传导和外泌体ASC释放的关键放大器。我们还观察到，暴露于含锰烟气的焊工的血浆外泌体比匹配对照组的血浆外泌体含有更多的ASC。在一起，这些结果表明，二价金属锰充当NLRP3炎性体信号传导和外泌体ASC释放的关键放大器。