Human NLRP1 and NLRP3 interact to drive inflammation in inflammosomopathies and inflammatory diseases

Abstract Inflammasomes are multiprotein complexes that form and activate after exposure to pathogenic microbes and host danger signals that trigger an inflammatory response. Although NLRP1 and NLRP3 inflammasomes share structural similarities and can be activated by similar stimuli, no evidence of heterotypic inflammasome assemblies has been reported. Here, we identify a unique interaction between NLRP1 and NLRP3 in human cells, forming a hybrid inflammasome, to drive inflammation. NLRP1 is essential for this hydrid inflammasome activation and NLRP3-mediated Caspase-1 activation and release of IL-1β and IL-18. The presence of the heterocomplex inflammasome was confirmed in blood samples from patients after kidney transplantation and is associated with inflammatory responses driven by NLRP3 and MEFV mutations that cause inflammasomopathies. Our findings reveal an unexpected level of intricacy in inflammasome composition, pinpointing hybrid targets that may pave the way for innovative pharmacological treatments for inflammatory disorders. Significance Statement Previous findings showed interactions between NLRP3 and NLRC4 or NLRP3 and NLRP11 showing that would be possible the interaction of the inflammasomes as supercomplexes and not working alone. Now, we show a new inflammasome heterocomplex inflammasome between NLRP1 and NLRP3 which is associated to the inflammatory profile in autoimmune diseases patietns and transplanted patients. These findings could open a new research topic for the design of dual inflammasomes inhibitors.