The non-canonical inflammasome is an emerging crucial player in the development of inflammatory and neurodegenerative diseases. It is activated by direct sensing of cytosolic lipopolysaccharide (LPS) by caspase-11 (CASP11), which then induces pyroptosis, an inflammatory form of regulated cell death. Here, we report that tyrosine kinase 2 (TYK2), a cytokine receptor-associated kinase, is a critical upstream regulator of CASP11. Absence of TYK2 or its kinase activity impairs the transcriptional induction of CASP11 in vitro and in vivo and protects mice from LPS-induced lethality. Lack of TYK2 or its enzymatic activity inhibits macrophage pyroptosis and impairs release of mature IL-1β and IL-18 specifically in response to intracellular LPS. Deletion of TYK2 in myeloid cells reduces LPS-induced IL-1β and IL-18 production in vivo, highlighting the importance of these cells in the inflammatory response to LPS. In support of our data generated with genetically engineered mice, pharmacological inhibition of TYK2 reduced LPS-induced upregulation of CASP11 in bone marrow-derived macrophages (BMDMs) and of its homolog CASP5 in human macrophages. Our study provides insights into the regulation of CASP11 in vivo and uncovered a novel link between TYK2 activity and CASP11-dependent inflammation.

非经典炎症小体是炎症和神经退行性疾病发展中新兴的关键参与者。它通过 caspase-11 (CASP11) 直接感应胞质脂多糖 (LPS) 来激活，然后诱导细胞焦亡，这是一种受调节的细胞死亡的炎症形式。在这里，我们报告酪氨酸激酶 2 (TYK2)，一种细胞因子受体相关激酶，是 CASP11 的关键上游调节因子。缺乏 TYK2 或其激酶活性会损害 CASP11 在体外和体内的转录诱导，并保护小鼠免受 LPS 诱导的致死性。缺乏 TYK2 或其酶活性会抑制巨噬细胞焦亡并损害成熟 IL-1β 和 IL-18 的释放，特别是对细胞内 LPS 的反应。骨髓细胞中 TYK2 的缺失降低了 LPS 诱导的体内 IL-1β 和 IL-18 的产生，强调这些细胞在对 LPS 的炎症反应中的重要性。为了支持我们用基因工程小鼠产生的数据，TYK2 的药理学抑制降低了 LPS 诱导的骨髓衍生巨噬细胞 (BMDM) 中 CASP11 及其同源物 CASP5 在人类巨噬细胞中的上调。我们的研究提供了对体内 CASP11 调节的见解，并揭示了 TYK2 活性与 CASP11 依赖性炎症之间的新联系。