How does purine metabolism control inflammatory responses?

Over-exuberant inflammasome activation drives the pathogenesis of numerous diseases, although the molecular basis for hyperactivation in many cases is poorly understood. Recent studies into an autoimmunity risk gene (FAMIN) have highlighted the importance of intracellular purine metabolism in tuning immune responses. FAMIN, a multifunctional enzyme, balances flux through purine nucleotide interconversion cycles in immune cells such as macrophages. I will investigate the hypothesis that purine metabolites generated by FAMIN, and biochemically related enzymes, control inflammasome activation to tune inflammatory responses. I will delineate how intrinsic purine metabolism shapes inflammasome activation in macrophages and intestinal epithelial cells. Through functional assays and metabolic flux studies, I will dissect the biochemical mechanisms controlling inflammasome activation in the context of perturbed intracellular purine metabolism. This will be complemented with microscopy-based approaches to investigate differences in inflammasome spatiotemporal organisation. I will explore the hypothesis that endogenous purine metabolism controls pyroptotic cell death, a process closely intertwined with inflammasome activation, and utilise targeted and unbiased approaches to uncover responsible molecular mechanisms. I will uncover how purine-controlled inflammasome activation drives in vivo phenotypic differences in sepsis and infection models. This will advance our understanding of fundamental processes driving maladaptive inflammatory responses in disease.