Inflammasomes are important sentinels of innate immune defense; they sense pathogens and induce the cell death of infected cells, playing key roles in inflammation, development, and cancer. Several inflammasome sensors detect and respond to specific pathogen- and damage-associated molecular patterns (PAMPs and DAMPs, respectively) by forming a multiprotein complex with the adapters ASC and caspase-1. During disease, cells are exposed to several PAMPs and DAMPs, leading to the concerted activation of multiple inflammasomes. However, the molecular mechanisms that integrate multiple inflammasome sensors to facilitate optimal host defense remain unknown. Here, we discovered that simultaneous inflammasome activation by multiple ligands triggered multiple types of programmed inflammatory cell death, and these effects could not be mimicked by treatment with a pure ligand of any single inflammasome. Furthermore, NLRP3, AIM2, NLRC4, and Pyrin were determined to be members of a large multiprotein complex, along with ASC, caspase-1, caspase-8, and RIPK3, and this complex drove PANoptosis. Furthermore, this multiprotein complex was released into the extracellular space and retained as multiple inflammasomes. Multiple extracellular inflammasome particles could induce inflammation after their engulfment by neighboring macrophages. Collectively, our findings define a previously unknown regulatory connection and molecular interaction between inflammasome sensors, which drives the assembly of a multiprotein complex that includes multiple inflammasome sensors and cell death regulators. The discovery of critical interactions among NLRP3, AIM2, NLRC4, and Pyrin represents a new paradigm in understanding the functions of these molecules in innate immunity and inflammasome biology as well as identifying new therapeutic targets for NLRP3-, AIM2-, NLRC4- and Pyrin-mediated diseases.

炎性小体是先天免疫防御的重要哨兵;它们感知病原体并诱导受感染细胞的细胞死亡，在炎症、发育和癌症中起关键作用。几种炎性小体传感器通过与接头 ASC 和 caspase-1 形成多蛋白复合物来检测和响应特定的病原体和损伤相关分子模式（分别为 PAMP 和 DAMP）。在疾病期间，细胞暴露于多种 PAMP 和 DAMP，导致多种炎性小体的协同激活。然而，整合多个炎性小体传感器以促进最佳宿主防御的分子机制仍然未知。在这里，我们发现多个配体同时激活炎性小体触发了多种类型的程序性炎症细胞死亡，并且这些效应不能通过用任何单个炎性小体的纯配体处理来模拟。此外，NLRP3 、 AIM2 、 NLRC4 和 Pyrin 与 ASC 、 caspase-1 、 caspase-8 和 RIPK3 一起被确定为一个大型多蛋白复合体的成员，该复合体驱动 PANoptosis。此外，这种多蛋白复合物被释放到细胞外间隙并保留为多个炎性小体。多个细胞外炎性小体颗粒在被邻近的巨噬细胞吞噬后可诱导炎症。总的来说，我们的研究结果定义了炎症小体传感器之间以前未知的调节联系和分子相互作用，这驱动了包括多个炎症小体传感器和细胞死亡调节因子在内的多蛋白复合物的组装。 NLRP3、AIM2、NLRC4 和 Pyrin 之间关键相互作用的发现代表了理解这些分子在先天免疫和炎性小体生物学中的功能以及确定 NLRP3、AIM2、NLRC4 和 Pyrin 介导的疾病的新治疗靶点的新范式。