2. Academic Validation
  3. Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells

Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells

  • Nature. 2023 Aug 9. doi: 10.1038/s41586-023-06409-6.
Liliana M Sanmarco 1,  Joseph M Rone 1 2,  Carolina M Polonio 1,  Gonzalo Fernandez Lahore 1 2,  Federico Giovannoni 1,  Kylynne Ferrara 1,  Cristina Gutierrez-Vazquez 1,  Ning Li 3,  Anna Sokolovska 3,  Agustin Plasencia 1,  Camilo Faust Akl 1,  Payal Nanda 1,  Evelin S Heck 1,  Zhaorong Li 1,  Hong-Gyun Lee 1,  Chun-Cheih Chao 1,  Claudia M Rejano-Gordillo 1,  Pedro H Fonseca-Castro 1,  Tomer Illouz 1,  Mathias Linnerbauer 1,  Jessica E Kenison 1,  Rocky M Barilla 1 2,  Daniel Farrenkopf 1,  Nikolas A Stevens 1,  Gavin Piester 1,  Elizabeth N Chung 1,  Lucas Dailey 4,  Vijay K Kuchroo 1 2,  David Hava 3,  Michael A Wheeler 1 4,  Clary Clish 4,  Roni Nowarski 1 2,  Eduardo Balsa 5,  Jose M Lora 3,  Francisco J Quintana 6 7
Affiliations

Affiliations

  • 1 Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA.
  • 2 Evergrande Center for Immunologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA.
  • 3 Synlogic Therapeutics, Cambridge, MA, USA.
  • 4 Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 5 Centro de Biología Molecular Severo Ochoa UAM-CSIC, Universidad Autónoma de Madrid, Madrid, Spain.
  • 6 Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA. fquintana@rics.bwh.harvard.edu.
  • 7 Broad Institute of MIT and Harvard, Cambridge, MA, USA. fquintana@rics.bwh.harvard.edu.
PMID: 37558878 DOI: 10.1038/s41586-023-06409-6
Abstract

Dendritic cells (DCs) have a role in the development and activation of self-reactive pathogenic T cells1,2. Genetic variants that are associated with the function of DCs have been linked to autoimmune disorders3,4, and DCs are therefore attractive therapeutic targets for such diseases. However, developing DC-targeted therapies for autoimmunity requires identification of the mechanisms that regulate DC function. Here, using single-cell and bulk transcriptional and metabolic analyses in combination with cell-specific gene perturbation studies, we identify a regulatory loop of negative feedback that operates in DCs to limit immunopathology. Specifically, we find that lactate, produced by activated DCs and Other immune cells, boosts the expression of NDUFA4L2 through a mechanism mediated by hypoxia-inducible factor 1α (HIF-1α). NDUFA4L2 limits the production of mitochondrial Reactive Oxygen Species that activate XBP1-driven transcriptional modules in DCs that are involved in the control of pathogenic autoimmune T cells. We also engineer a probiotic that produces lactate and suppresses T cell autoimmunity through the activation of HIF-1α-NDUFA4L2 signalling in DCs. In summary, we identify an immunometabolic pathway that regulates DC function, and develop a synthetic probiotic for its therapeutic activation.

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