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

  • bioRxiv. 2023 Mar 21:2023.03.17.532101. doi: 10.1101/2023.03.17.532101.
Liliana M Sanmarco ,  Joseph M Rone ,  Carolina M Polonio ,  Federico Giovannoni ,  Gonzalo Fernandez Lahore ,  Kylynne Ferrara ,  Cristina Gutierrez-Vazquez ,  Ning Li ,  Anna Sokolovska ,  Agustin Plasencia ,  Camilo Faust Akl ,  Payal Nanda ,  Evelin S Heck ,  Zhaorong Li ,  Hong-Gyun Lee ,  Chun-Cheih Chao ,  Claudia M Rejano-Gordillo ,  Pedro H Fonseca-Castro ,  Tomer Illouz ,  Mathias Linnerbauer ,  Jessica E Kenison ,  Rocky M Barilla ,  Daniel Farrenkopf ,  Gavin Piester ,  Lucas Dailey ,  Vijay K Kuchroo ,  David Hava ,  Michael A Wheeler ,  Clary Clish ,  Roni Nowarski ,  Eduardo Balsa ,  Jose M Lora ,  Francisco J Quintana
PMID: 36993446 DOI: 10.1101/2023.03.17.532101
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-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.

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