A cell is delimited by numerous borders that define specific organelles. The walls of some organelles are particularly robust, such as in mitochondria or endoplasmic reticulum, but some are more fluid such as in phase-separated stress granules. Either way, all organelles can be damaged at times, leading their contents to leak out into the surrounding environment. Therefore, an elegant way to construct an innate immune defence system is to recognize host molecules that do not normally reside within a particular compartment. Here, we provide several examples where organellar homeostasis is lost, leading to the activation of a specific innate immune sensor; these include NLRP3 activation owing to a disrupted trans-Golgi network, Pyrin activation due to cytoskeletal damage, and cGAS–STING activation following the leakage of nuclear or mitochondrial DNA. Frequently, organelle damage is observed downstream of pathogenic infection but it can also occur in sterile settings as associated with auto-inflammatory disease. Therefore, understanding organellar homeostasis is central to efforts that will identify new innate immune pathways, and therapeutics that balance organellar homeostasis, or target the breakdown pathways that trigger innate immune sensors, could be useful treatments for infection and chronic inflammatory diseases.

细胞由许多定义特定细胞器的边界界定。一些细胞器的壁特别坚固，例如在线粒体或内质网中，但有些细胞器的流动性更强，例如相分离的应激颗粒。无论哪种方式，所有细胞器有时都会受损，导致其内容物泄漏到周围环境中。因此，构建先天免疫防御系统的一种优雅方法是识别通常不驻留在特定隔间内的宿主分子。在这里，我们提供了几个失去细胞器稳态导致特定先天免疫传感器激活的例子；这些包括由于跨高尔基体网络中断导致的 NLRP3 激活，由于细胞骨架损伤导致的 Pyrin 激活，核或线粒体 DNA 泄漏后的 cGAS–STING 激活。通常，在病原体感染的下游观察到细胞器损伤，但它也可能发生在与自身炎症性疾病相关的无菌环境中。因此，了解细胞器内稳态对于确定新的先天免疫途径的努力至关重要，而平衡细胞器内稳态或针对触发先天免疫传感器的分解途径的疗法可能是治疗感染和慢性炎症性疾病的有效方法。