The concept of innate immunity has been expanded to recognize environmental pathogens other than microbial components. However, whether and how the innate immunity is initiated by epithelium in response to environmental physical challenges such as low humidity and high osmolarity in an autoimmune disease, dry eye, is still largely unknown. Using two experimental dry eye models, primary human corneal epithelial cultures exposed to hyperosmolarity and mouse ocular surface facing desiccating stress, we uncovered novel innate immunity pathway by ocular surface epithelium, where oxidized mitochondrial DNA induces imbalanced activation of NLRP3/NLRP6 inflammasomes via stimulation of caspase-8 and BRCC36 in response to environmental stress. Activated NLRP3 with suppressed NLRP6 stimulates caspase-1 activation that leads to IL-1β and IL-18 maturation and secretion. NLRP3-independent caspase-8 noncanonically activates caspase-1 via reciprocal regulation of NLRP3/NLRP6-mediated inflammasomes. Reactive oxygen species-induced mitochondrial DNA oxidative damage and BRCC36 deubiquitinating activity provide a missing link and mechanism by which innate immunity responds to environmental stress via caspase-8-involved NLRP3/NLRP6 inflammasomes.

中文翻译：

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线粒体DNA氧化可通过活化干眼中的caspase-8和BRCC36诱导NLRP3 / NLRP6炎性小体活性失衡。

先天免疫的概念已扩展到识别除微生物成分以外的环境病原体。然而，对于环境免疫物理性挑战，如自身免疫性疾病干眼中的低湿度和高渗透压，上皮是否以及如何引发先天免疫仍然是未知的。我们使用两种实验性干眼模型，即暴露于高渗的主要人类角膜上皮培养物和面临干燥压力的小鼠眼表，发现了眼表上皮的新型先天免疫途径，其中氧化的线粒体DNA通过刺激胱天蛋白酶刺激了NLRP3 / NLRP6炎性小体的失衡活化。 -8和BRCC36应对环境压力。NLRP6受到抑制的活化NLRP3刺激caspase-1活化，导致IL-1β和IL-18的成熟和分泌。不依赖于NLRP3的caspase-8通过相互调节NLRP3 / NLRP6介导的炎症小体非典型地激活caspase-1。活性氧诱导的线粒体DNA氧化损伤和BRCC36去泛素化活性提供了缺失的联系和机制，通过这种联系和机制，先天性免疫通过caspase-8参与的NLRP3 / NLRP6炎性小体对环境胁迫作出反应。