Unanticipated Loss of Inflammasomes in Birds

Abstract Inflammasomes are multiprotein complexes that form in response to ligands originating from pathogens as well as alterations of normal cell physiology caused by infection or tissue damage. These structures engage a robust inflammatory immune response that eradicates environmental microbes before they cause disease, and slow the growth of bona fide pathogens. Despite their undeniable utility in immunity, inflammasomes are radically reduced in birds. Perhaps most surprising is that, within all birds, NLRP3 is retained, while its signaling adapter ASC is lost, suggesting that NLRP3 signals via a novel unknown adapter. Crocodilian reptiles and turtles, which share a more recent common ancestor with birds, retain many of the lost inflammasome components, indicating that the deletion of inflammasomes occurred after birds diverged from crocodiles. Some bird lineages have even more extensive inflammasome loss, with songbirds continuing to pare down their inflammasomes until only NLRP3 and CARD8 remain. Remarkably, songbirds have lost caspase-1 but retain the downstream targets of caspase-1: IL-1β, IL-18, and the YVAD-linker encoding gasdermin A. This suggests that inflammasomes can signal through alternative proteases to activate cytokine maturation and pyroptosis in songbirds. These observations may reveal new contexts of activation that may be relevant to mammalian inflammasomes and may suggest new avenues of research to uncover the enigmatic nature of the poorly understood NLRP3 inflammasome.