Detection of cytosolic DNA constitutes a central event in the context of numerous infectious and sterile inflammatory conditions. Recent studies have uncovered a bipartite mode of cytosolic DNA recognition, in which the cGAS-STING axis triggers antiviral immunity, whereas AIM2 triggers inflammasome activation. Here, we show that AIM2 is dispensable for DNA-mediated inflammasome activation in human myeloid cells. Instead, detection of cytosolic DNA by the cGAS-STING axis induces a cell death program initiating potassium efflux upstream of NLRP3. Forward genetics identified regulators of lysosomal trafficking to modulate this cell death program, and subsequent studies revealed that activated STING traffics to the lysosome, where it triggers membrane permeabilization and thus lysosomal cell death (LCD). Importantly, the cGAS-STING-NLRP3 pathway constitutes the default inflammasome response during viral and bacterial infections in human myeloid cells. We conclude that targeting the cGAS-STING-LCD-NLRP3 pathway will ameliorate pathology in inflammatory conditions that are associated with cytosolic DNA sensing.

中文翻译：

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人类骨髓细胞中的 DNA 炎症小体由 NLRP3 上游的 STING 细胞死亡程序启动。

细胞溶质 DNA 的检测构成了许多感染性和无菌炎症条件下的中心事件。最近的研究揭示了胞质 DNA 识别的二分模式，其中 cGAS-STING 轴触发抗病毒免疫，而 AIM2 触发炎性体激活。在这里，我们表明 AIM2 对于人类骨髓细胞中 DNA 介导的炎性体激活是可有可无的。相反，通过 cGAS-STING 轴检测细胞溶质 DNA 会诱导细胞死亡程序，从而启动 NLRP3 上游的钾外流。正向遗传学确定了溶酶体运输的调节剂来调节这种细胞死亡程序，随后的研究表明，激活的 STING 运输到溶酶体，在那里它触发膜透化，从而引发溶酶体细胞死亡 (LCD)。重要的，cGAS-STING-NLRP3 通路构成了人类骨髓细胞中病毒和细菌感染期间的默认炎症小体反应。我们得出结论，靶向 cGAS-STING-LCD-NLRP3 途径将改善与细胞溶质 DNA 传感相关的炎症条件下的病理学。