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

Liliana M. Sanmarco, Joseph M. Rone, Carolina M. Polonio, Gonzalo Fernandez Lahore, Federico Giovannoni, 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, Nikolas A. Stevens, Gavin Piester, Elizabeth N. Chung, Lucas Dailey, Vijay K. Kuchroo, David Hava, Michael A. Wheeler, Clary Clish, Roni Nowarski, Eduardo Balsa, Jose M. Lora and Francisco J. Quintana ()
Additional contact information
Liliana M. Sanmarco: Harvard Medical School, Brigham and Women’s Hospital
Joseph M. Rone: Harvard Medical School, Brigham and Women’s Hospital
Carolina M. Polonio: Harvard Medical School, Brigham and Women’s Hospital
Gonzalo Fernandez Lahore: Harvard Medical School, Brigham and Women’s Hospital
Federico Giovannoni: Harvard Medical School, Brigham and Women’s Hospital
Kylynne Ferrara: Harvard Medical School, Brigham and Women’s Hospital
Cristina Gutierrez-Vazquez: Harvard Medical School, Brigham and Women’s Hospital
Ning Li: Synlogic Therapeutics
Anna Sokolovska: Synlogic Therapeutics
Agustin Plasencia: Harvard Medical School, Brigham and Women’s Hospital
Camilo Faust Akl: Harvard Medical School, Brigham and Women’s Hospital
Payal Nanda: Harvard Medical School, Brigham and Women’s Hospital
Evelin S. Heck: Harvard Medical School, Brigham and Women’s Hospital
Zhaorong Li: Harvard Medical School, Brigham and Women’s Hospital
Hong-Gyun Lee: Harvard Medical School, Brigham and Women’s Hospital
Chun-Cheih Chao: Harvard Medical School, Brigham and Women’s Hospital
Claudia M. Rejano-Gordillo: Harvard Medical School, Brigham and Women’s Hospital
Pedro H. Fonseca-Castro: Harvard Medical School, Brigham and Women’s Hospital
Tomer Illouz: Harvard Medical School, Brigham and Women’s Hospital
Mathias Linnerbauer: Harvard Medical School, Brigham and Women’s Hospital
Jessica E. Kenison: Harvard Medical School, Brigham and Women’s Hospital
Rocky M. Barilla: Harvard Medical School, Brigham and Women’s Hospital
Daniel Farrenkopf: Harvard Medical School, Brigham and Women’s Hospital
Nikolas A. Stevens: Harvard Medical School, Brigham and Women’s Hospital
Gavin Piester: Harvard Medical School, Brigham and Women’s Hospital
Elizabeth N. Chung: Harvard Medical School, Brigham and Women’s Hospital
Lucas Dailey: Broad Institute of MIT and Harvard
Vijay K. Kuchroo: Harvard Medical School, Brigham and Women’s Hospital
David Hava: Synlogic Therapeutics
Michael A. Wheeler: Harvard Medical School, Brigham and Women’s Hospital
Clary Clish: Broad Institute of MIT and Harvard
Roni Nowarski: Harvard Medical School, Brigham and Women’s Hospital
Eduardo Balsa: Universidad Autónoma de Madrid
Jose M. Lora: Synlogic Therapeutics
Francisco J. Quintana: Harvard Medical School, Brigham and Women’s Hospital

Nature, 2023, vol. 620, issue 7975, 881-889

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41586-023-06409-6

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