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 LinnerbauerJessica 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, Francisco J. Quintana

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Dendritic cells (DCs) have a role in the development and activation of self-reactive pathogenic T cells 1,2. Genetic variants that are associated with the function of DCs have been linked to autoimmune disorders 3,4, 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.

Original languageEnglish
Pages (from-to)881-889
Number of pages9
JournalNature
Volume620
Issue number7975
Early online date9 Aug 2023
DOIs
StatePublished - 24 Aug 2023
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature Limited.

Fingerprint

Dive into the research topics of 'Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells'. Together they form a unique fingerprint.

Cite this