2. Academic Validation
  3. Engineered probiotics limit CNS autoimmunity by stabilizing HIF-1α in dendritic cells

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.

Figures
Products