| Autor: |
Sanmarco, Liliana M., Rone, Joseph M., Polonio, Carolina M., Giovannoni, Federico, Lahore, Gonzalo Fernandez, Ferrara, Kylynne, Gutierrez-Vazquez, Cristina, Li, Ning, Sokolovska, Anna, Plasencia, Agustin, Akl, Camilo Faust, Nanda, Payal, Heck, Evelin S., Li, Zhaorong, Lee, Hong-Gyun, Chao, Chun-Cheih, Rejano-Gordillo, Claudia M., Fonseca-Castro, Pedro H., Illouz, Tomer, Linnerbauer, Mathias, Kenison, Jessica E., Barilla, Rocky M., Farrenkopf, Daniel, Piester, Gavin, Dailey, Lucas, Kuchroo, Vijay K., Hava, David, Wheeler, Michael A., Clish, Clary, Nowarski, Roni, Balsa, Eduardo, Lora, Jose M., Quintana, Francisco J. |
| Rok vydání: |
2023 |
| Předmět: |
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| Zdroj: |
bioRxiv |
| Popis: |
SummaryDendritic 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-1α. 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-1α/NDUFA4L2 signaling in DCs. In summary, we identified an immunometabolic pathway that regulates DC function, and developed a synthetic probiotic for its therapeutic activation. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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