Aging-Associated TNF Production Primes Inflammasome Activation and NLRP3-Related Metabolic Disturbances

Accumulating evidence suggests that the activation of the innate branch of the immune system plays a pivotal role in the induction and perpetuation of metabolic and aging-related diseases. In this context, the NLRP3 inflammasome pathway has been identified as an important driver of sterile inflammatory processes. De novo protein synthesis of NLRP3 induced by signals such as TLR ligands or TNF is a prerequisite for sustained NLRP3 mediated caspase-1 cleavage and inflammasome activation. Here, we demonstrate in aged mice that spontaneously elevated TNF represents a critical priming signal that functions to control NLRP3 inflammasome activation. Elevated systemic TNF levels were responsible for increased NLRP3 expression and caspase-1 activity in adipose tissues and liver. TNF dependent, spontaneous inflammasome activity in aged mice resulted in impaired glucose tolerance that could be attributed to peripheral insulin resistance. Altogether, these results implicate that TNF-driven NLRP3 expression constitutes an important checkpoint that regulates inflammasome activation, presumably by additional signals such as aging-associated DAMPs.