The NLRP3 inflammasome, a critical component of the innate immune system, induces caspase-1 activation and interleukin-1β maturation and drives cell fate toward pyroptosis. However, the mechanism of NLRP3 inflammasome activation still remains elusive. Here we provide evidence that AKT regulates NLRP3 inflammasome activation. Upon NLRP3 activation, AKT activity is inhibited by second stimulus-induced reactive oxygen species. In contrast, AKT activation leads to NLRP3 inhibition and improved mitochondrial fitness. Mechanistically, AKT induces the phosphorylation of the DDX3X (DEAD-box helicase 3, X-linked), a recently identified NLRP3 inflammasome component, and impairs the interaction between DDX3X and NLRP3. Furthermore, an AKT agonist reduces NLRP3-dependent inflammation in two in vivo models of LPS-induced sepsis and Alum-induced peritonitis. Altogether, our study highlights an important role of AKT in controlling NLRP3 inflammasome activation.

中文翻译：

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AKT 通过诱导 DDX3X 磷酸化来控制 NLRP3 炎症小体激活

NLRP3 炎症小体是先天免疫系统的关键组成部分，可诱导 caspase-1 激活和白细胞介素 1β 成熟，并促使细胞命运趋向于细胞焦亡。然而，NLRP3 炎症小体激活的机制仍然难以捉摸。在这里，我们提供了 AKT 调节 NLRP3 炎症小体激活的证据。NLRP3 激活后，AKT 活性被第二次刺激诱导的活性氧抑制。相比之下，AKT 激活会导致 NLRP3 抑制和改善线粒体健康。从机制上讲，AKT 诱导 DDX3X（DEAD-box 解旋酶 3，X 连锁）磷酸化，这是一种最近发现的 NLRP3 炎性体成分，并损害 DDX3X 和 NLRP3 之间的相互作用。此外，AKT 激动剂可减少体内两种 NLRP3 依赖性炎症LPS 诱导的败血症和明矾诱导的腹膜炎模型。总之，我们的研究强调了 AKT 在控制 NLRP3 炎症小体激活方面的重要作用。