Department of Pediatrics, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
Institute for Medical Informatics and Biometry, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
Cell Rep. 2020 Feb 25;30(8):2501-2511.e5. doi: 10.1016/j.celrep.2020.01.090.
Pro-inflammatory caspase-1 is a key player in innate immunity. Caspase-1 processes interleukin (IL)-1β and IL-18 to their mature forms and triggers pyroptosis. These caspase-1 functions are linked to its enzymatic activity. However, loss-of-function missense mutations in CASP1 do not prevent autoinflammation in patients, despite decreased IL-1β production. In vitro data suggest that enzymatically inactive caspase-1 drives inflammation via enhanced nuclear factor κB (NF-κB) activation, independent of IL-1β processing. Here, we report two mouse models of enzymatically inactive caspase-1-C284A, demonstrating the relevance of this pathway in vivo. In contrast to Casp1 mice, caspase-1-C284A mice show pronounced hypothermia and increased levels of the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α) and IL-6 when challenged with lipopolysaccharide (LPS). Caspase-1-C284A signaling is RIP2 dependent and mediated by TNF-α but independent of the NLRP3 inflammasome. LPS-stimulated whole blood from patients carrying loss-of-function missense mutations in CASP1 secretes higher amounts of TNF-α. Taken together, these results reveal non-canonical caspase-1 signaling in vivo.
促炎型半胱天冬酶-1（caspase-1）是先天免疫中的关键因子。caspase-1 可将白细胞介素（IL）-1β和 IL-18 加工成熟，并引发细胞焦亡。这些 caspase-1 功能与其酶活性相关。然而，尽管 IL-1β的产生减少，CASP1 中的失活功能错义突变并不能阻止患者的自身炎症。体外数据表明，酶失活的 caspase-1 通过增强核因子 κB（NF-κB）的激活来驱动炎症，而不依赖于 IL-1β的加工。在这里，我们报告了两种酶失活 caspase-1-C284A 的小鼠模型，证明了该途径在体内的相关性。与 Casp1 小鼠相比，当用脂多糖（LPS）刺激时，caspase-1-C284A 小鼠表现出明显的体温过低和促炎细胞因子肿瘤坏死因子-α（TNF-α）和 IL-6 水平升高。caspase-1-C284A 信号传导依赖于 RIP2，由 TNF-α介导，但不依赖于 NLRP3 炎性小体。来自携带 CASP1 失活功能错义突变的患者的 LPS 刺激全血分泌更多的 TNF-α。总之，这些结果揭示了体内非典型 caspase-1 信号传导。
