Abstract Inflammasome-mediated caspase-1 activation facilitates innate immune control of Plasmodium in the liver, thereby limiting the incidence and severity of clinical malaria. However, caspase-1 processing occurs incompletely in both mouse and human hepatocytes and precludes the generation of mature IL-1β or IL-18, unlike in other cells. Why this is so or how it impacts Plasmodium control in the liver has remained unknown. We show that an inherently reduced expression of the inflammasome adaptor molecule apoptosis-associated specklike protein containing CARD (ASC) is responsible for the incomplete proteolytic processing of caspase-1 in murine hepatocytes. Transgenically enhancing ASC expression in hepatocytes enabled complete caspase-1 processing, enhanced pyroptotic cell death, maturation of the proinflammatory cytokines IL-1β and IL-18 that was otherwise absent, and better overall control of Plasmodium infection in the liver of mice. This, however, impeded the protection offered by live attenuated antimalarial vaccination. Tempering ASC expression in mouse macrophages, on the other hand, resulted in incomplete processing of caspase-1. Our work shows how caspase-1 activation and function in host cells are fundamentally defined by ASC expression and offers a potential new pathway to create better disease and vaccination outcomes by modifying the latter.

中文翻译：

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ASC 表达的固有减少限制了肝细胞中 Caspase-1 的加工并促进疟原虫感染

摘要炎症小体介导的 caspase-1 激活促进肝脏中疟原虫的先天免疫控制，从而限制临床疟疾的发病率和严重程度。然而，与其他细胞不同，小鼠和人类肝细胞中 caspase-1 的加工都不完全，并且阻止了成熟 IL-1β 或 IL-18 的产生。为什么会这样或者它如何影响肝脏中的疟原虫控制仍然未知。我们发现，含有 CARD (ASC) 的炎性体接头分子凋亡相关斑点样蛋白 (ASC) 的表达固有减少是导致小鼠肝细胞中 caspase-1 蛋白水解加工不完全的原因。通过转基因增强肝细胞中的 ASC 表达，可以实现完整的 caspase-1 加工、增强细胞焦亡、促炎细胞因子 IL-1β 和 IL-18 的成熟（否则这些细胞因子是不存在的），并更好地全面控制小鼠肝脏中的疟原虫感染。然而，这阻碍了减毒活抗疟疾疫苗提供的保护。另一方面，调节小鼠巨噬细胞中的 ASC 表达会导致 caspase-1 的加工不完全。我们的工作展示了宿主细胞中 caspase-1 的激活和功能如何从根本上由 ASC 表达定义，并提供了一条潜在的新途径，通过修改后者来创造更好的疾病和疫苗接种结果。