Human natural killer cells can activate NLRP1 and NLRP3 inflammasomes and drives pyroptosis

Innate immunity relies on inflammasomes as key components, defending the host against diverse harmful stimuli by orchestrating the release of pro-inflammatory cytokines and initiating pyroptotic cell death. While extensively studied in myeloid cells, the involvement of natural killer (NK) cells in inflammatory responses through inflammasome signaling remains underexplored. In this study, we elucidate the activation of the inflammasome sensors NLRP1 and NLRP3 in human primary NK cells upon treatment with nigericin and blockade of dipeptidyl peptidases (DPP) using Talabostat (Val-boroPro). Our findings demonstrate the induction of pyroptotic cell death in a subset of NK cells following these stimuli, characterized by the cleavage and activation of gasdermin D, a lytic pore-forming protein. Moreover, we observe the release of lactate dehydrogenase (LDH) and small amounts of interleukin-18 (IL-18). Notably, differential responses are noted between CD56 ^dim and CD56 ^bright NK cell subsets following pro-inflammatory stimulation. Furthermore, analysis of samples from patients with renal dysfunction reveals sustained inflammasome activation in NK cells, particularly NLRP1 and NLRP3, with a tendency towards a more pro-inflammatory phenotype shortly post-kidney transplantation. These findings underscore the significance of considering NK cells in the context of inflammation studies.