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Engineered probiotics limit CNS autoimmunity by stabilizing HIF-1α in dendritic cells

Sanmarco, L. M.; Rone, J. M.; Polonio, C. M.; Giovannoni, F.; Fernandez Lahore, G.; Ferrara, K.; Gutierrez-Vazquez, C.; Li, N.; Sokolovska, A.; Plasencia, A.; Faust Akl, C.; Nanda, P.; Heck, E. S.; Li, Z.; Lee, H.-G.; Chao, C.-C.; Rejano-Gordillo, C. M.; Fonseca-Castro, P. H.; Illouz, T.; Linnerbauer, M.; Kenison, J. E.; Barilla, R. M.; Farrenkopf, D.; Piester, G.; Dailey, L.; Kuchroo, V. K.; Hava, D.; Wheeler, M. A.; Clish, C.; Nowarski, R.; Balsa, E.; Lora, J. M.; Quintana, F. J.

2023-03-21 immunology
10.1101/2023.03.17.532101 bioRxiv
Show abstract

Dendritic cells (DCs) control the generation of self-reactive pathogenic T cells. Thus, DCs are considered attractive therapeutic targets for autoimmune diseases. Using single-cell and bulk transcriptional and metabolic analyses in combination with cell-specific gene perturbation studies we identified a negative feedback regulatory pathway that operates in DCs to limit immunopathology. Specifically, we found that lactate, produced by activated DCs and other immune cells, boosts NDUFA4L2 expression through a mechanism mediated by HIF-1. NDUFA4L2 limits the production of mitochondrial reactive oxygen species that activate XBP1-driven transcriptional modules in DCs involved in the control of pathogenic autoimmune T cells. Moreover, we engineered a probiotic that produces lactate and suppresses T-cell autoimmunity in the central nervous system via the activation of HIF-1/NDUFA4L2 signaling in DCs. In summary, we identified an immunometabolic pathway that regulates DC function, and developed a synthetic probiotic for its therapeutic activation.

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