Citation

4626 total record number 0 records this year

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

Sanmarco, LM;Rone, JM;Polonio, CM;Giovannoni, F;Lahore, GF;Ferrara, K;Gutierrez-Vazquez, C;Li, N;Sokolovska, A;Plasencia, A;Akl, CF;Nanda, P;Heck, ES;Li, Z;Lee, HG;Chao, CC;Rejano-Gordillo, CM;Fonseca-Castro, PH;Illouz, T;Linnerbauer, M;Kenison, JE;Barilla, RM;Farrenkopf, D;Piester, G;Dailey, L;Kuchroo, VK;Hava, D;Wheeler, MA;Clish, C;Nowarski, R;Balsa, E;Lora, JM;Quintana, FJ;

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.