The role of lipids in inflammasome activation remains underappreciated. The phospholipid, platelet-activating factor (PAF), exerts multiple physiological functions by binding to a G protein–coupled seven-transmembrane receptor (PAFR). PAF is associated with a number of inflammatory disorders, yet the molecular mechanism underlying its proinflammatory function remains to be fully elucidated. We show that multiple PAF isoforms and PAF-like lipids can activate the inflammasome, resulting in IL-1β and IL-18 maturation. This is dependent on NLRP3, ASC, caspase-1, and NEK7, but not on NLRC4, NLRP1, NLRP6, AIM2, caspase-11, or GSDMD. Inflammasome activation by PAF also requires potassium efflux and calcium influx but not lysosomal cathepsin or mitochondrial reactive oxygen species. PAF exacerbates peritonitis partly through inflammasome activation, but PAFR is dispensable for PAF-induced inflammasome activation in vivo or in vitro. These findings reveal that PAF represents a damage-associated signal that activates the canonical inflammasome independently of PAFR and provides an explanation for the ineffectiveness of PAFR antagonist in blocking PAF-mediated inflammation in the clinic.

脂质在炎症小体激活中的作用仍未得到充分认识。磷脂、血小板活化因子 (PAF) 通过与 G 蛋白偶联的七跨膜受体 (PAFR) 结合发挥多种生理功能。PAF 与许多炎症性疾病有关，但其促炎功能的分子机制仍有待充分阐明。我们表明多种 PAF 同种型和 PAF 样脂质可以激活炎性体，导致 IL-1β 和 IL-18 成熟。这取决于 NLRP3、ASC、caspase-1 和 NEK7，但不取决于 NLRC4、NLRP1、NLRP6、AIM2、caspase-11 或 GS​​DMD。PAF 激活炎性体也需要钾外流和钙内流，但不需要溶酶体组织蛋白酶或线粒体活性氧。PAF 部分通过炎症小体激活加剧腹膜炎，但 PAFR 对于 PAF 诱导的体内或体外炎症小体激活是不必要的。这些发现表明，PAF 代表了一种与损伤相关的信号，它独立于 PAFR 激活典型的炎症小体，并解释了 PAFR 拮抗剂在临床上阻断 PAF 介导的炎症的无效性。