Metabolic regulation of granulomatous inflammation by tryptophan catabolism

The pathological hallmark of sarcoidosis is the formation of granulomas driven by the accumulation of activated macrophages and T-cells, and the production of proinflammatory cytokines. Current evidence indicates that granuloma formation depends on genetic, microbial and environmental factors. Indoleamine 2,3-dioxygenase 1 (IDO1) is an immunoregulatory enzyme that catalyzes the rate-limiting step of tryptophan catabolism along the kynurenine pathway to produce immunomodulatory metabolites, being mostly expressed in antigen-presenting cells and associated with the generation of tolerogenic T-cells. In this study, we aimed to investigate if IDO1 activity could represent a missing link explaining the pathological features of granuloma formation in sarcoidosis. To achieve this, we used different experimental <italic>in vitro</italic> and <italic>in vivo</italic> models of granuloma formation, including peripheral blood mononuclear cells sourced from patients with loss-of-function single nucleotide polymorphisms (SNPs) and gene-deleted mice. Our findings reveal a correlation between the rs7820268 SNP in IDO1 and the risk of developing sarcoidosis (OR, 1.81; 95% CI 1.27, 2.57, p=0.0016). Moreover, patients with the risk genotype showed an increased accumulation of T-cells, macrophages and neutrophils in the bronchoalveolar lavage at diagnosis. Consistently, our <italic>in vivo</italic> model of granuloma formation showed that IDO1 expression is upregulated during granuloma formation, and that mice lacking IDO1 exhibited enhanced recruitment of leukocytes and overall increased inflammation. These results suggest that IDO1 plays a role in regulating immune cell recruitment during granuloma formation in sarcoidosis and possibly as a factor in disease progression.