Friday, April 19, 2024
4/19/2024
Project Summary/Abstract Pre-clinical Rheumatoid Arthritis (RA) is a period in which systemic autoimmunity develops in the years prior to onset of clinically apparent disease. Here, we aim to define the mechanisms leading to pre-clinical autoimmunity, which could inform the design of therapies to block these pathways and prevent RA. Our group has been integral in identifying and investigating the “mucosal origins” hypothesis of RA, utilizing the collagen-induced arthritis (CIA) model to demonstrate the requirement of the microbiome for disease development. We recently identified a bacterial-derived tryptophan metabolite, indole, as a key regulator of autoimmunity in this model. Depletion of either the microbiome (using broad-spectrum antibiotics) or dietary tryptophan is protective against CIA, and supplementation with indole in either setting reverses this protection. This indole-CIA model provides, for the first time, a model in which a single bacterial metabolite is sufficient for disease development. Based on our preliminary findings that Th17 cells and inflammatory cytokine production (especially IL-6) are elevated in this indole-CIA model, I hypothesize that indole is a bioactive metabolite that promotes CIA by skewing Th17 cell differentiation and stimulating antigen presenting cells (APCs) to produce IL-6. The experiments outlined in this proposal are designed to define the effects of indole on CIA. Aim 1 will determine the effect of indole on CD4 effector T cell responses, both in the indole-CIA model and in a model of antigen-specific T cell responses utilizing OT-II transgenic mice. Aim 2 will then identify the source of and requirement for indole-mediated IL-6 production. I will utilize combined single cell RNA/ATACseq to identify the cell subsets and signaling pathways in which indole induces IL-6 production. Finally, I will test the requirement for dendritic cell (DC)-mediated IL-6 production in indole-CIA. Successful completion of these aims will (1) define the cell subsets and functions affected by indole in the indole-CIA model, which will allow for future mechanistic studies to better define and modulate this process, (2) define the role of DC-derived IL-6 in CIA, which has never been shown, and (3) generate hypotheses to later identify the signaling pathways affected by indole stimulation, which will be necessary to understand the mechanisms by which indole incites autoimmunity. Altogether, these findings will fill a critical knowledge gap regarding the role of the microbiome in the development of inflammatory arthritis. Furthermore, through these studies I will become an expert in mucosal immunology, learn to design and test rigorous hypotheses, and become proficient in cutting-edge bioinformatic techniques through analysis of the RNA/ATACseq data generated in Aim 2. The training gained through this proposal will enable me to be well- positioned for a research fellowship in rheumatology and apply skills needed for a successful K08 in the future.
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