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; Francisco J. Quintana

doi:10.1038/s41586-023-06409-6

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 journal › Article › peer-review

49 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 language	English
Pages (from-to)	881-889
Number of pages	9
Journal	Nature
Volume	620
Issue number	7975
Early online date	9 Aug 2023
DOIs	https://doi.org/10.1038/s41586-023-06409-6
State	Published - 24 Aug 2023
Externally published	Yes

Bibliographical note

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

Funding

This work was supported by grants NS102807, ES02530, ES029136 and AI126880 from the National Institutes of Health (NIH); RG4111A1 and JF2161-A-5 from the National Multiple Sclerosis Society; RSG-14-198-01-LIB from the American Cancer Society; and PA-160408459 from the International Progressive MS Alliance (to F.J.Q.). C.M.P. was supported by a fellowship from FAPESP BEPE (2019/13731-0) and by the Herbert R. & Jeanne C. Mayer Foundation; G.F.L. received support from a grant from the Swedish Research Council (2021-06735); C.G.-V. was supported by an Alfonso Martin Escudero Foundation postdoctoral fellowship and by a postdoctoral fellowship (ALTF 610-2017) from the European Molecular Biology Organization; C.-C.C. received support from a postdoctoral research abroad program (104-2917-I-564-024) from the Ministry of Science and Technology, Taiwan; C.M.R.-G. was supported by a predoctoral F.P.U. fellowship from the Ministry of Economy and Competitiveness and by the European Union FEDERER program; M.A.W. was supported by NIH (1K99NS114111, F32NS101790 and T32CA207201), the Program in Interdisciplinary Neuroscience and the Women’s Brain Initiative at Brigham and Women’s Hospital; T.I. was supported by an EMBO postdoctoral fellowship (ALTF: 1009–2021) and H.-G.L. was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2021R1A6A3A14039088). We thank L. Glimcher and J. R. Cubillos Ruiz for sharing ItgaxXbp1 mice; S. McSorley for providing the S. typhimurium strain; H. Xu and M. Lehtinen for providing training on CSF extraction; all members of the F.J.Q. laboratory for advice and discussions; R. Krishnan for technical assistance with flow cytometry studies; and the NeuroTechnology Studio at Brigham and Women’s Hospital for providing access to Seahorse instruments. Cre f lox

Funders	Funder number
FAPESP BEPE	2019/13731-0
Herbert R. & Jeanne C. Mayer Foundation
National Institutes of Health	RG4111A1, JF2161-A-5
American Cancer Society	PA-160408459
National Multiple Sclerosis Society	RSG-14-198-01-LIB
European Molecular Biology Organization	104-2917-I-564-024, 1009–2021
Fundación Alfonso Martín Escudero	ALTF 610-2017
International Progressive MS Alliance
European Commission	T32CA207201, F32NS101790, 1K99NS114111
Ministry of Education	2021R1A6A3A14039088
Ministerio de Economía y Competitividad
National Research Foundation of Korea
Vetenskapsrådet	2021-06735
Ministry of Science and Technology, Taiwan

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Sanmarco, L. M., Rone, J. M., Polonio, C. M., Fernandez Lahore, G., Giovannoni, F., Ferrara, K., Gutierrez-Vazquez, C., Li, N., Sokolovska, A., Plasencia, A., Faust Akl, C., Nanda, P., Heck, E. S., Li, Z., Lee, H. G., Chao, C. C., Rejano-Gordillo, C. M., Fonseca-Castro, P. H., Illouz, T., ... Quintana, F. J. (2023). Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells. Nature, 620(7975), 881-889. https://doi.org/10.1038/s41586-023-06409-6

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title = "Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells",

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.",

author = "Sanmarco, {Liliana M.} and Rone, {Joseph M.} and Polonio, {Carolina M.} and {Fernandez Lahore}, Gonzalo and Federico Giovannoni and Kylynne Ferrara and Cristina Gutierrez-Vazquez and Ning Li and Anna Sokolovska and Agustin Plasencia and {Faust Akl}, Camilo and Payal Nanda and Heck, {Evelin S.} and Zhaorong Li and Lee, {Hong Gyun} and Chao, {Chun Cheih} and Rejano-Gordillo, {Claudia M.} and Fonseca-Castro, {Pedro H.} and Tomer Illouz and Mathias Linnerbauer and Kenison, {Jessica E.} and Barilla, {Rocky M.} and Daniel Farrenkopf and Stevens, {Nikolas A.} and Gavin Piester and Chung, {Elizabeth N.} and Lucas Dailey and Kuchroo, {Vijay K.} and David Hava and Wheeler, {Michael A.} and Clary Clish and Roni Nowarski and Eduardo Balsa and Lora, {Jose M.} and Quintana, {Francisco J.}",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2023",

month = aug,

day = "24",

doi = "10.1038/s41586-023-06409-6",

language = "אנגלית",

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Sanmarco, LM, Rone, JM, Polonio, CM, Fernandez Lahore, G, Giovannoni, F, Ferrara, K, Gutierrez-Vazquez, C, Li, N, Sokolovska, A, Plasencia, A, Faust Akl, C, Nanda, P, Heck, ES, Li, Z, Lee, HG, Chao, CC, Rejano-Gordillo, CM, Fonseca-Castro, PH, Illouz, T, Linnerbauer, M, Kenison, JE, Barilla, RM, Farrenkopf, D, Stevens, NA, Piester, G, Chung, EN, Dailey, L, Kuchroo, VK, Hava, D, Wheeler, MA, Clish, C, Nowarski, R, Balsa, E, Lora, JM & Quintana, FJ 2023, 'Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells', Nature, vol. 620, no. 7975, pp. 881-889. https://doi.org/10.1038/s41586-023-06409-6

TY - JOUR

T1 - Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells

AU - Sanmarco, Liliana M.

AU - Rone, Joseph M.

AU - Polonio, Carolina M.

AU - Fernandez Lahore, Gonzalo

AU - Giovannoni, Federico

AU - Ferrara, Kylynne

AU - Gutierrez-Vazquez, Cristina

AU - Li, Ning

AU - Sokolovska, Anna

AU - Plasencia, Agustin

AU - Faust Akl, Camilo

AU - Nanda, Payal

AU - Heck, Evelin S.

AU - Li, Zhaorong

AU - Lee, Hong Gyun

AU - Chao, Chun Cheih

AU - Rejano-Gordillo, Claudia M.

AU - Fonseca-Castro, Pedro H.

AU - Illouz, Tomer

AU - Linnerbauer, Mathias

AU - Kenison, Jessica E.

AU - Barilla, Rocky M.

AU - Farrenkopf, Daniel

AU - Stevens, Nikolas A.

AU - Piester, Gavin

AU - Chung, Elizabeth N.

AU - Dailey, Lucas

AU - Kuchroo, Vijay K.

AU - Hava, David

AU - Wheeler, Michael A.

AU - Clish, Clary

AU - Nowarski, Roni

AU - Balsa, Eduardo

AU - Lora, Jose M.

AU - Quintana, Francisco J.

PY - 2023/8/24

Y1 - 2023/8/24

N2 - 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.

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

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