PMID- 37558878
OWN - NLM
STAT- MEDLINE
DCOM- 20230826
LR  - 20240510
IS  - 1476-4687 (Electronic)
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 620
IP  - 7975
DP  - 2023 Aug
TI  - Lactate limits CNS autoimmunity by stabilizing HIF-1alpha in dendritic cells.
PG  - 881-889
LID - 10.1038/s41586-023-06409-6 [doi]
AB  - 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 1alpha (HIF-1alpha). 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-1alpha-NDUFA4L2 
      signalling in DCs. In summary, we identify an immunometabolic pathway that 
      regulates DC function, and develop a synthetic probiotic for its therapeutic 
      activation.
CI  - (c) 2023. The Author(s), under exclusive licence to Springer Nature Limited.
FAU - Sanmarco, Liliana M
AU  - Sanmarco LM
AD  - Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and 
      Women's Hospital, Boston, MA, USA.
FAU - Rone, Joseph M
AU  - Rone JM
AUID- ORCID: 0009-0001-9130-0249
AD  - Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and 
      Women's Hospital, Boston, MA, USA.
AD  - Evergrande Center for Immunologic Diseases, Harvard Medical School, Brigham and 
      Women's Hospital, Boston, MA, USA.
FAU - Polonio, Carolina M
AU  - Polonio CM
AUID- ORCID: 0000-0003-0460-0161
AD  - Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and 
      Women's Hospital, Boston, MA, USA.
FAU - Fernandez Lahore, Gonzalo
AU  - Fernandez Lahore G
AD  - Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and 
      Women's Hospital, Boston, MA, USA.
AD  - Evergrande Center for Immunologic Diseases, Harvard Medical School, Brigham and 
      Women's Hospital, Boston, MA, USA.
FAU - Giovannoni, Federico
AU  - Giovannoni F
AD  - Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and 
      Women's Hospital, Boston, MA, USA.
FAU - Ferrara, Kylynne
AU  - Ferrara K
AD  - Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and 
      Women's Hospital, Boston, MA, USA.
FAU - Gutierrez-Vazquez, Cristina
AU  - Gutierrez-Vazquez C
AUID- ORCID: 0000-0002-3846-4631
AD  - Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and 
      Women's Hospital, Boston, MA, USA.
FAU - Li, Ning
AU  - Li N
AD  - Synlogic Therapeutics, Cambridge, MA, USA.
FAU - Sokolovska, Anna
AU  - Sokolovska A
AUID- ORCID: 0000-0002-1216-696X
AD  - Synlogic Therapeutics, Cambridge, MA, USA.
FAU - Plasencia, Agustin
AU  - Plasencia A
AUID- ORCID: 0000-0002-7415-0947
AD  - Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and 
      Women's Hospital, Boston, MA, USA.
FAU - Faust Akl, Camilo
AU  - Faust Akl C
AD  - Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and 
      Women's Hospital, Boston, MA, USA.
FAU - Nanda, Payal
AU  - Nanda P
AD  - Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and 
      Women's Hospital, Boston, MA, USA.
FAU - Heck, Evelin S
AU  - Heck ES
AD  - Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and 
      Women's Hospital, Boston, MA, USA.
FAU - Li, Zhaorong
AU  - Li Z
AUID- ORCID: 0000-0002-5268-6986
AD  - Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and 
      Women's Hospital, Boston, MA, USA.
FAU - Lee, Hong-Gyun
AU  - Lee HG
AUID- ORCID: 0000-0001-5960-5504
AD  - Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and 
      Women's Hospital, Boston, MA, USA.
FAU - Chao, Chun-Cheih
AU  - Chao CC
AUID- ORCID: 0000-0003-4108-2658
AD  - Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and 
      Women's Hospital, Boston, MA, USA.
FAU - Rejano-Gordillo, Claudia M
AU  - Rejano-Gordillo CM
AUID- ORCID: 0000-0003-4586-5975
AD  - Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and 
      Women's Hospital, Boston, MA, USA.
FAU - Fonseca-Castro, Pedro H
AU  - Fonseca-Castro PH
AD  - Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and 
      Women's Hospital, Boston, MA, USA.
FAU - Illouz, Tomer
AU  - Illouz T
AUID- ORCID: 0000-0003-4123-6469
AD  - Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and 
      Women's Hospital, Boston, MA, USA.
FAU - Linnerbauer, Mathias
AU  - Linnerbauer M
AUID- ORCID: 0000-0002-5528-5141
AD  - Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and 
      Women's Hospital, Boston, MA, USA.
FAU - Kenison, Jessica E
AU  - Kenison JE
AD  - Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and 
      Women's Hospital, Boston, MA, USA.
FAU - Barilla, Rocky M
AU  - Barilla RM
AD  - Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and 
      Women's Hospital, Boston, MA, USA.
AD  - Evergrande Center for Immunologic Diseases, Harvard Medical School, Brigham and 
      Women's Hospital, Boston, MA, USA.
FAU - Farrenkopf, Daniel
AU  - Farrenkopf D
AD  - Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and 
      Women's Hospital, Boston, MA, USA.
FAU - Stevens, Nikolas A
AU  - Stevens NA
AD  - Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and 
      Women's Hospital, Boston, MA, USA.
FAU - Piester, Gavin
AU  - Piester G
AUID- ORCID: 0000-0001-8413-7298
AD  - Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and 
      Women's Hospital, Boston, MA, USA.
FAU - Chung, Elizabeth N
AU  - Chung EN
AD  - Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and 
      Women's Hospital, Boston, MA, USA.
FAU - Dailey, Lucas
AU  - Dailey L
AUID- ORCID: 0000-0003-3204-9565
AD  - Broad Institute of MIT and Harvard, Cambridge, MA, USA.
FAU - Kuchroo, Vijay K
AU  - Kuchroo VK
AUID- ORCID: 0000-0001-7177-2110
AD  - Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and 
      Women's Hospital, Boston, MA, USA.
AD  - Evergrande Center for Immunologic Diseases, Harvard Medical School, Brigham and 
      Women's Hospital, Boston, MA, USA.
FAU - Hava, David
AU  - Hava D
AUID- ORCID: 0000-0002-9200-1566
AD  - Synlogic Therapeutics, Cambridge, MA, USA.
FAU - Wheeler, Michael A
AU  - Wheeler MA
AUID- ORCID: 0000-0002-0689-6384
AD  - Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and 
      Women's Hospital, Boston, MA, USA.
AD  - Broad Institute of MIT and Harvard, Cambridge, MA, USA.
FAU - Clish, Clary
AU  - Clish C
AUID- ORCID: 0000-0001-8259-9245
AD  - Broad Institute of MIT and Harvard, Cambridge, MA, USA.
FAU - Nowarski, Roni
AU  - Nowarski R
AD  - Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and 
      Women's Hospital, Boston, MA, USA.
AD  - Evergrande Center for Immunologic Diseases, Harvard Medical School, Brigham and 
      Women's Hospital, Boston, MA, USA.
FAU - Balsa, Eduardo
AU  - Balsa E
AD  - Centro de Biologia Molecular Severo Ochoa UAM-CSIC, Universidad Autonoma de 
      Madrid, Madrid, Spain.
FAU - Lora, Jose M
AU  - Lora JM
AD  - Synlogic Therapeutics, Cambridge, MA, USA.
FAU - Quintana, Francisco J
AU  - Quintana FJ
AUID- ORCID: 0000-0001-8156-0736
AD  - Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and 
      Women's Hospital, Boston, MA, USA. fquintana@rics.bwh.harvard.edu.
AD  - Broad Institute of MIT and Harvard, Cambridge, MA, USA. 
      fquintana@rics.bwh.harvard.edu.
LA  - eng
GR  - R01 MH130458/MH/NIMH NIH HHS/United States
GR  - P30 DK040561/DK/NIDDK NIH HHS/United States
GR  - R01 NS102807/NS/NINDS NIH HHS/United States
GR  - K99 NS114111/NS/NINDS NIH HHS/United States
GR  - R01 AI126880/AI/NIAID NIH HHS/United States
GR  - F32 NS101790/NS/NINDS NIH HHS/United States
GR  - R01 NS129778/NS/NINDS NIH HHS/United States
GR  - R01 ES029136/ES/NIEHS NIH HHS/United States
GR  - R00 NS114111/NS/NINDS NIH HHS/United States
PT  - Journal Article
DEP - 20230809
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 33X04XA5AT (Lactic Acid)
RN  - 0 (NDUFA4L2 protein, human)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (XBP1 protein, human)
RN  - EC 3.2.1.108 (Lactase)
SB  - IM
UOF - bioRxiv. 2023 Mar 21;:. PMID: 36993446
CIN - Nat Rev Immunol. 2023 Oct;23(10):615. PMID: 37667054
MH  - Humans
MH  - *Autoimmune Diseases/immunology/metabolism/prevention & control
MH  - Autoimmunity
MH  - *Central Nervous System/cytology/immunology/pathology
MH  - *Dendritic Cells/immunology/metabolism
MH  - *Hypoxia-Inducible Factor 1, alpha Subunit/chemistry/genetics/metabolism
MH  - *Lactic Acid/metabolism
MH  - Probiotics/therapeutic use
MH  - Reactive Oxygen Species/metabolism
MH  - T-Lymphocytes/immunology
MH  - Feedback, Physiological
MH  - Lactase/genetics/metabolism
MH  - Single-Cell Analysis
PMC - PMC10725186
MID - NIHMS1941773
COIS- Competing interests N.L., A.S., D.H. and J.M.L. were employees of Synlogic 
      Therapeutics during some of this study. The remaining authors declare no 
      competing interests.
EDAT- 2023/08/10 00:42
MHDA- 2023/08/25 06:42
PMCR- 2023/12/16
CRDT- 2023/08/09 23:28
PHST- 2021/11/09 00:00 [received]
PHST- 2023/07/06 00:00 [accepted]
PHST- 2023/08/25 06:42 [medline]
PHST- 2023/08/10 00:42 [pubmed]
PHST- 2023/08/09 23:28 [entrez]
PHST- 2023/12/16 00:00 [pmc-release]
AID - 10.1038/s41586-023-06409-6 [pii]
AID - 10.1038/s41586-023-06409-6 [doi]
PST - ppublish
SO  - Nature. 2023 Aug;620(7975):881-889. doi: 10.1038/s41586-023-06409-6. Epub 2023 
      Aug 9.