Platelet activating factor as a novel danger signal for activation of NLRP3 inflammasome

Abstract

Abstract Platelet activating factor (PAF) is a biologically active phospholipid that promotes pathophysiological inflammation through binding to a unique G-protein-coupled seven transmembrane receptor (PAFR). Increased PAF level has been correlated with a number of inflammatory disorders, yet the molecular mechanism underlying the pro-inflammatory function of PAF remains incompletely elucidated. Here we showed PAF activates canonical NLRP3 inflammasome, resulting in ASC oligomerization, caspase-1 processing, and IL-1β and IL-18 maturation. PAF-induced IL-1β maturation is abrogated in macrophage from Nlrp3−/−, Asc−/−, Caspase-1−/− mice, but not Nlrc4−/−, Nlrp1−/−, Aim2−/−, Caspase-11−/− mice. In addition, NEK7, a new component of the NLRP3 inflammasome, is also essential for PAF induced IL-1β maturation. PAF activation of the NLRP3 inflammasome is dependent on calcium influx, potassium efflux, but independent of lysosome cathepsin, mitochondrial reactive oxygen species (ROS), and necroptosis. Surprisingly, PAFR is not essential for PAF induced NLRP3 inflammasome activation. Physiologically, PAF induced shock is protected in NLRP3 inflammasome component deficient mice. Together, our findings reveal a new PAFR independent pathway for detecting PAF which represents an unprecedented danger signaling function of PAF, and provide new insight for understanding the pathogenesis of PAF-mediated inflammatory disorders.