Bacterial catabolism of dietary tryptophan into indole enhances DC-mediated pro-inflammatory responses in autoimmunity 3709

Abstract Description Microbial tryptophan catabolism is altered in various autoimmune diseases, but the impact on host pathophysiology remains a significant knowledge gap. We previously demonstrated that a tryptophan-low (TL) diet protected mice from collagen-induced arthritis (CIA). Supplementation with the microbial-derived tryptophan metabolite indole restored disease severity by inducing Th17 responses and pathogenic autoantibodies. In this study, we hypothesized that indole’s effect on Th17 responses is mediated by intestinal mononuclear phagocytes (MNPs). We first assessed lamina propria and mesenteric lymph node (MLN) MNP subsets from CIA mice, which showed increased IL-6 and IL-23 production by MLN cDC2s in the TL+Indole group compared to TL+Vehicle. Stimulation of bone marrow derived dendritic cells (BMDCs) with indole + LPS resulted in significantly higher levels of IL-6 and IL-23 compared to LPS alone and could differentiate naive T cells into Rorgt+ Th17 cells. To identify transcriptional pathways induced by indole supplementation, bulk RNA sequencing of MLN CD11c+ DCs from indole-CIA mice revealed a migratory and pro-inflammatory signature, including increased IL-6 and IL-23 production in TL+Indole mice. Together, these data provide evidence for a mechanism by which indole, in conjunction with microbial (TLR) stimuli, enhances production of pro-inflammatory cytokines that could lead to the enhanced autoimmunity that we previously observed from bacterial metabolism of tryptophan. Funding Sources Supported by NIH grants R01AR075933 (NIAMS), P30AR079369 (NIAMS), T32AI007405 (NIAID), F30AI174817 (NIAID) Topic Categories Basic Autoimmunity (BA)