Taurine metabolism is associated with inflammasome activation via the taurine transporter

Abstract

The intersection of immunology and metabolism, known as immunometabolism, explores the interactions between immune responses and metabolic changes. Inflammasomes form an integral part of the innate immune system and are equipped with NLR or ALR receptors capable of detecting a wide array of stimuli triggered by infections or cellular damage. Upon activation, these inflammasomes are involved in the release of inflammatory cytokines and can trigger a regulated type of cell death known as pyroptosis. Like other immune responses, inflammasome activation also induces changes in metabolic pathways such as the tricarboxylic acid (TCA) cycle. However, the role of other metabolic pathways in response to activation of inflammasomes remains less explored. Here, by employing a metabolomic approach on murine macrophages, I found that activation of inflammasomes (NLRP3, AIM2 or NLRC4) induced metabolic shifts not only within the TCA cycle, but also extends its impact to sulphur metabolism. Furthermore, through a rigorous cross-species analysis that compared human and mouse responses, I uncovered a notable downregulation of taurine metabolism following NLRP3 activation. This intriguing discovery highlighted a conserved regulatory mechanism and identified intracellular depletion of taurine and hypotaurine as a putative checkpoint in NLRP3 activation pathway. Using two distinct approaches, a direct supplementation of taurine or hypotaurine, and inhibition of taurine transporter prior to NLRP3 activation, showed a significant decrease in IL-1β release in a caspase-1 independent manner. The clinical significance of these findings was underlined by the observation of a similar downregulation of taurine metabolism in individuals affected by tuberculosis-associated immune reconstitution inflammatory syndrome, which is known to be inflammasome-driven. This convergence of in vitro observations with clinical data further emphasizes the importance of inflammasome-mediated metabolic alterations and their potential impact on disease pathogenesis. These findings hold considerable potential for guiding future research aimed at unravelling the intricate cross-talk between inflammation and metabolism, with far-reaching implications for the design of targeted therapeutic strategies to counter aberrant inflammasome activation.