Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells
- Autores
- Sanmarco, Liliana Maria; Rone, Joseph M.; Polonio, Carolina M.; Fernandez Lahore, Gonzalo; Giovannoni, Federico; Ferrara, Kylynne; Gutierrez Vazquez, Cristina; Li, Ning; Sokolovska, Anna; Plasencia, Agustin; Faust Akl, Camilo; Nanda, Payal; Heck, Evelyn Sabrina; Li, Zhaorong; Lee, Hong Gyun; Chao, Chun Cheih; Rejano Gordillo, Claudia M.; Fonseca Castro, Pedro H.; Illouz, Tomer; Linnerbauer, Mathias; Kenison, Jessica E.; Barilla, Rocky M.; Farrenkopf, Daniel; Stevens, Nikolas A.; Piester, Gavin; Clish, Clary; Nowarski, Roni; Balsa, Eduardo; Lora, Jose M.; Quintana, Francisco Javier
- Año de publicación
- 2023
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- 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.
Fil: Sanmarco, Liliana Maria. Harvard Medical School; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Rone, Joseph M.. Harvard Medical School; Estados Unidos
Fil: Polonio, Carolina M.. Harvard Medical School; Estados Unidos
Fil: Fernandez Lahore, Gonzalo. Harvard Medical School; Estados Unidos
Fil: Giovannoni, Federico. Harvard Medical School; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Ferrara, Kylynne. Harvard Medical School; Estados Unidos
Fil: Gutierrez Vazquez, Cristina. Harvard Medical School; Estados Unidos
Fil: Li, Ning. Synlogic Therapeutics; Estados Unidos
Fil: Sokolovska, Anna. Synlogic Therapeutics; Estados Unidos
Fil: Plasencia, Agustin. Harvard Medical School; Estados Unidos
Fil: Faust Akl, Camilo. Harvard Medical School; Estados Unidos
Fil: Nanda, Payal. Harvard Medical School; Estados Unidos
Fil: Heck, Evelyn Sabrina. Harvard Medical School; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Li, Zhaorong. Harvard Medical School; Estados Unidos
Fil: Lee, Hong Gyun. Harvard Medical School; Estados Unidos
Fil: Chao, Chun Cheih. Harvard Medical School; Estados Unidos
Fil: Rejano Gordillo, Claudia M.. Harvard Medical School; Estados Unidos
Fil: Fonseca Castro, Pedro H.. Harvard Medical School; Estados Unidos
Fil: Illouz, Tomer. Harvard Medical School; Estados Unidos
Fil: Linnerbauer, Mathias. Harvard Medical School; Estados Unidos
Fil: Kenison, Jessica E.. Harvard Medical School; Estados Unidos
Fil: Barilla, Rocky M.. Harvard Medical School; Estados Unidos
Fil: Farrenkopf, Daniel. Harvard Medical School; Estados Unidos
Fil: Stevens, Nikolas A.. Harvard Medical School; Estados Unidos
Fil: Piester, Gavin. Harvard Medical School; Estados Unidos
Fil: Clish, Clary. Broad Institute of MIT and Harvard; Estados Unidos
Fil: Nowarski, Roni. Harvard Medical School; Estados Unidos
Fil: Balsa, Eduardo. Universidad Autónoma de Madrid; España
Fil: Lora, Jose M.. Synlogic Therapeutics; Estados Unidos
Fil: Quintana, Francisco Javier. Harvard Medical School; Estados Unidos. Broad Institute of MIT and Harvard; Estados Unidos - Materia
-
Lactate
CNS
HIF-1α
dendritic cells - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
- Repositorio
.jpg)
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/264616
Ver los metadatos del registro completo
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Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cellsSanmarco, Liliana MariaRone, Joseph M.Polonio, Carolina M.Fernandez Lahore, GonzaloGiovannoni, FedericoFerrara, KylynneGutierrez Vazquez, CristinaLi, NingSokolovska, AnnaPlasencia, AgustinFaust Akl, CamiloNanda, PayalHeck, Evelyn SabrinaLi, ZhaorongLee, Hong GyunChao, Chun CheihRejano Gordillo, Claudia M.Fonseca Castro, Pedro H.Illouz, TomerLinnerbauer, MathiasKenison, Jessica E.Barilla, Rocky M.Farrenkopf, DanielStevens, Nikolas A.Piester, GavinClish, ClaryNowarski, RoniBalsa, EduardoLora, Jose M.Quintana, Francisco JavierLactateCNSHIF-1αdendritic cellshttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Dendritic 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.Fil: Sanmarco, Liliana Maria. Harvard Medical School; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Rone, Joseph M.. Harvard Medical School; Estados UnidosFil: Polonio, Carolina M.. Harvard Medical School; Estados UnidosFil: Fernandez Lahore, Gonzalo. Harvard Medical School; Estados UnidosFil: Giovannoni, Federico. Harvard Medical School; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ferrara, Kylynne. Harvard Medical School; Estados UnidosFil: Gutierrez Vazquez, Cristina. Harvard Medical School; Estados UnidosFil: Li, Ning. Synlogic Therapeutics; Estados UnidosFil: Sokolovska, Anna. Synlogic Therapeutics; Estados UnidosFil: Plasencia, Agustin. Harvard Medical School; Estados UnidosFil: Faust Akl, Camilo. Harvard Medical School; Estados UnidosFil: Nanda, Payal. Harvard Medical School; Estados UnidosFil: Heck, Evelyn Sabrina. Harvard Medical School; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Li, Zhaorong. Harvard Medical School; Estados UnidosFil: Lee, Hong Gyun. Harvard Medical School; Estados UnidosFil: Chao, Chun Cheih. Harvard Medical School; Estados UnidosFil: Rejano Gordillo, Claudia M.. Harvard Medical School; Estados UnidosFil: Fonseca Castro, Pedro H.. Harvard Medical School; Estados UnidosFil: Illouz, Tomer. Harvard Medical School; Estados UnidosFil: Linnerbauer, Mathias. Harvard Medical School; Estados UnidosFil: Kenison, Jessica E.. Harvard Medical School; Estados UnidosFil: Barilla, Rocky M.. Harvard Medical School; Estados UnidosFil: Farrenkopf, Daniel. Harvard Medical School; Estados UnidosFil: Stevens, Nikolas A.. Harvard Medical School; Estados UnidosFil: Piester, Gavin. Harvard Medical School; Estados UnidosFil: Clish, Clary. Broad Institute of MIT and Harvard; Estados UnidosFil: Nowarski, Roni. Harvard Medical School; Estados UnidosFil: Balsa, Eduardo. Universidad Autónoma de Madrid; EspañaFil: Lora, Jose M.. Synlogic Therapeutics; Estados UnidosFil: Quintana, Francisco Javier. Harvard Medical School; Estados Unidos. Broad Institute of MIT and Harvard; Estados UnidosNature Publishing Group2023-08info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/vnd.openxmlformats-officedocument.wordprocessingml.documentapplication/pdfhttp://hdl.handle.net/11336/264616Sanmarco, Liliana Maria; Rone, Joseph M.; Polonio, Carolina M.; Fernandez Lahore, Gonzalo; Giovannoni, Federico; et al.; Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells; Nature Publishing Group; Nature; 620; 7975; 8-2023; 881-8890028-0836CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://pubmed.ncbi.nlm.nih.gov/37558878/info:eu-repo/semantics/altIdentifier/doi/10.1038/s41586-023-06409-6info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T15:02:09Zoai:ri.conicet.gov.ar:11336/264616instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-15 15:02:09.67CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
| dc.title.none.fl_str_mv |
Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells |
| title |
Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells |
| spellingShingle |
Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells Sanmarco, Liliana Maria Lactate CNS HIF-1α dendritic cells |
| title_short |
Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells |
| title_full |
Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells |
| title_fullStr |
Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells |
| title_full_unstemmed |
Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells |
| title_sort |
Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells |
| dc.creator.none.fl_str_mv |
Sanmarco, Liliana Maria Rone, Joseph M. Polonio, Carolina M. Fernandez Lahore, Gonzalo Giovannoni, Federico Ferrara, Kylynne Gutierrez Vazquez, Cristina Li, Ning Sokolovska, Anna Plasencia, Agustin Faust Akl, Camilo Nanda, Payal Heck, Evelyn Sabrina Li, Zhaorong Lee, Hong Gyun Chao, Chun Cheih Rejano Gordillo, Claudia M. Fonseca Castro, Pedro H. Illouz, Tomer Linnerbauer, Mathias Kenison, Jessica E. Barilla, Rocky M. Farrenkopf, Daniel Stevens, Nikolas A. Piester, Gavin Clish, Clary Nowarski, Roni Balsa, Eduardo Lora, Jose M. Quintana, Francisco Javier |
| author |
Sanmarco, Liliana Maria |
| author_facet |
Sanmarco, Liliana Maria Rone, Joseph M. Polonio, Carolina M. Fernandez Lahore, Gonzalo Giovannoni, Federico Ferrara, Kylynne Gutierrez Vazquez, Cristina Li, Ning Sokolovska, Anna Plasencia, Agustin Faust Akl, Camilo Nanda, Payal Heck, Evelyn Sabrina Li, Zhaorong Lee, Hong Gyun Chao, Chun Cheih Rejano Gordillo, Claudia M. Fonseca Castro, Pedro H. Illouz, Tomer Linnerbauer, Mathias Kenison, Jessica E. Barilla, Rocky M. Farrenkopf, Daniel Stevens, Nikolas A. Piester, Gavin Clish, Clary Nowarski, Roni Balsa, Eduardo Lora, Jose M. Quintana, Francisco Javier |
| author_role |
author |
| author2 |
Rone, Joseph M. Polonio, Carolina M. Fernandez Lahore, Gonzalo Giovannoni, Federico Ferrara, Kylynne Gutierrez Vazquez, Cristina Li, Ning Sokolovska, Anna Plasencia, Agustin Faust Akl, Camilo Nanda, Payal Heck, Evelyn Sabrina Li, Zhaorong Lee, Hong Gyun Chao, Chun Cheih Rejano Gordillo, Claudia M. Fonseca Castro, Pedro H. Illouz, Tomer Linnerbauer, Mathias Kenison, Jessica E. Barilla, Rocky M. Farrenkopf, Daniel Stevens, Nikolas A. Piester, Gavin Clish, Clary Nowarski, Roni Balsa, Eduardo Lora, Jose M. Quintana, Francisco Javier |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
Lactate CNS HIF-1α dendritic cells |
| topic |
Lactate CNS HIF-1α dendritic cells |
| purl_subject.fl_str_mv |
https://purl.org/becyt/ford/1.6 https://purl.org/becyt/ford/1 |
| dc.description.none.fl_txt_mv |
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. Fil: Sanmarco, Liliana Maria. Harvard Medical School; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Rone, Joseph M.. Harvard Medical School; Estados Unidos Fil: Polonio, Carolina M.. Harvard Medical School; Estados Unidos Fil: Fernandez Lahore, Gonzalo. Harvard Medical School; Estados Unidos Fil: Giovannoni, Federico. Harvard Medical School; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Ferrara, Kylynne. Harvard Medical School; Estados Unidos Fil: Gutierrez Vazquez, Cristina. Harvard Medical School; Estados Unidos Fil: Li, Ning. Synlogic Therapeutics; Estados Unidos Fil: Sokolovska, Anna. Synlogic Therapeutics; Estados Unidos Fil: Plasencia, Agustin. Harvard Medical School; Estados Unidos Fil: Faust Akl, Camilo. Harvard Medical School; Estados Unidos Fil: Nanda, Payal. Harvard Medical School; Estados Unidos Fil: Heck, Evelyn Sabrina. Harvard Medical School; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Li, Zhaorong. Harvard Medical School; Estados Unidos Fil: Lee, Hong Gyun. Harvard Medical School; Estados Unidos Fil: Chao, Chun Cheih. Harvard Medical School; Estados Unidos Fil: Rejano Gordillo, Claudia M.. Harvard Medical School; Estados Unidos Fil: Fonseca Castro, Pedro H.. Harvard Medical School; Estados Unidos Fil: Illouz, Tomer. Harvard Medical School; Estados Unidos Fil: Linnerbauer, Mathias. Harvard Medical School; Estados Unidos Fil: Kenison, Jessica E.. Harvard Medical School; Estados Unidos Fil: Barilla, Rocky M.. Harvard Medical School; Estados Unidos Fil: Farrenkopf, Daniel. Harvard Medical School; Estados Unidos Fil: Stevens, Nikolas A.. Harvard Medical School; Estados Unidos Fil: Piester, Gavin. Harvard Medical School; Estados Unidos Fil: Clish, Clary. Broad Institute of MIT and Harvard; Estados Unidos Fil: Nowarski, Roni. Harvard Medical School; Estados Unidos Fil: Balsa, Eduardo. Universidad Autónoma de Madrid; España Fil: Lora, Jose M.. Synlogic Therapeutics; Estados Unidos Fil: Quintana, Francisco Javier. Harvard Medical School; Estados Unidos. Broad Institute of MIT and Harvard; Estados Unidos |
| description |
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. |
| publishDate |
2023 |
| dc.date.none.fl_str_mv |
2023-08 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo |
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article |
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publishedVersion |
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http://hdl.handle.net/11336/264616 Sanmarco, Liliana Maria; Rone, Joseph M.; Polonio, Carolina M.; Fernandez Lahore, Gonzalo; Giovannoni, Federico; et al.; Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells; Nature Publishing Group; Nature; 620; 7975; 8-2023; 881-889 0028-0836 CONICET Digital CONICET |
| url |
http://hdl.handle.net/11336/264616 |
| identifier_str_mv |
Sanmarco, Liliana Maria; Rone, Joseph M.; Polonio, Carolina M.; Fernandez Lahore, Gonzalo; Giovannoni, Federico; et al.; Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells; Nature Publishing Group; Nature; 620; 7975; 8-2023; 881-889 0028-0836 CONICET Digital CONICET |
| dc.language.none.fl_str_mv |
eng |
| language |
eng |
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info:eu-repo/semantics/altIdentifier/url/https://pubmed.ncbi.nlm.nih.gov/37558878/ info:eu-repo/semantics/altIdentifier/doi/10.1038/s41586-023-06409-6 |
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Nature Publishing Group |
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Nature Publishing Group |
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dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar |
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