Fatty acid oxidation of alternatively activated macrophages prevents foam cell formation, but Mycobacterium tuberculosis counteracts this process via HIF-1α activation
- Autores
- Genoula, Melanie; Marin Franco, Jose Luis; Maio, Mariano; Dolotowicz, Belén; Ferreyra Compagnucci, Malena María; Milillo, María Ayelén; Mascarau, Rémi; Moraña, Eduardo José; Palmero, Domingo Juan; Matteo, Mario José; Fuentes, Federico; López, Beatriz; Barrionuevo, Paula; Neyrolles, Olivier; Cougoule, Céline; Lugo Villarino, Geanncarlo; Vérollet, Christel; Sasiain, María del Carmen; Balboa, Luciana
- Año de publicación
- 2020
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- The ability of Mycobacterium tuberculosis (Mtb) to persist inside host cells relies on metabolic adaptation, like the accumulation of lipid bodies (LBs) in the so-called foamy macrophages (FM), which are favorable to Mtb. The activation state of macrophages is tightly associated to different metabolic pathways, such as lipid metabolism, but whether differentiation towards FM differs between the macrophage activation profiles remains unclear. Here, we aimed to elucidate whether distinct macrophage activation states exposed to a tuberculosis-associated microenvironment or directly infected with Mtb can form FM. We showed that the triggering of signal transducer and activator of transcription 6 (STAT6) in interleukin (IL)-4-activated human macrophages (M(IL-4)) prevents FM formation induced by pleural effusion from patients with tuberculosis. In these cells, LBs are disrupted by lipolysis, and the released fatty acids enter the β-oxidation (FAO) pathway fueling the generation of ATP in mitochondria. Accordingly, murine alveolar macrophages, which exhibit a predominant FAO metabolism, are less prone to become FM than bone marrow derived-macrophages. Interestingly, direct infection of M(IL-4) macrophages with Mtb results in the establishment of aerobic glycolytic pathway and FM formation, which could be prevented by FAO activation or inhibition of the hypoxia-inducible factor 1-alpha (HIF-1α)-induced glycolytic pathway. In conclusion, our results demonstrate that Mtb has a remarkable capacity to induce FM formation through the rewiring of metabolic pathways in human macrophages, including the STAT6-driven alternatively activated program. This study provides key insights into macrophage metabolism and pathogen subversion strategies.
Fil: Genoula, Melanie. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Centre National de la Recherche Scientifique; Francia. International Associated Laboratory; Argentina
Fil: Marin Franco, Jose Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Centre National de la Recherche Scientifique; Francia. International Associated Laboratory; Argentina
Fil: Maio, Mariano. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Dolotowicz, Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Ferreyra Compagnucci, Malena María. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Milillo, María Ayelén. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Mascarau, Rémi. Université de Toulouse; Francia. Centre National de la Recherche Scientifique; Francia
Fil: Moraña, Eduardo José. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; Argentina
Fil: Palmero, Domingo Juan. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; Argentina
Fil: Matteo, Mario José. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Tisioneumonología "raúl F. Vaccarezza".; Argentina
Fil: Fuentes, Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: López, Beatriz. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud "Dr. C. G. Malbrán"; Argentina
Fil: Barrionuevo, Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Neyrolles, Olivier. International Associated Laboratory; Argentina. Université de Toulouse; Francia. Centre National de la Recherche Scientifique; Francia
Fil: Cougoule, Céline. Centre National de la Recherche Scientifique; Francia. Université de Toulouse; Francia. International Associated Laboratory; Argentina
Fil: Lugo Villarino, Geanncarlo. Centre National de la Recherche Scientifique; Francia. Université de Toulouse; Francia. International Associated Laboratory; Argentina
Fil: Vérollet, Christel. Centre National de la Recherche Scientifique; Francia. International Associated Laboratory; Argentina. Université de Toulouse; Francia
Fil: Sasiain, María del Carmen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Centre National de la Recherche Scientifique; Francia. International Associated Laboratory; Argentina
Fil: Balboa, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Centre National de la Recherche Scientifique; Francia. International Associated Laboratory; Argentina - Materia
-
BETA OXIDATION OF FATTY ACIDS
FOAMY MACROPHAGES
HYPOXIA INDUCIBLE FACTOR 1ALPHA
INTERLEUKIN 4
IMMUNOMETABOLISM
MYCOBACTERIUM TUBERCULOSIS
SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 6 - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by/2.5/ar/
- Repositorio
.jpg)
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/117595
Ver los metadatos del registro completo
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Fatty acid oxidation of alternatively activated macrophages prevents foam cell formation, but Mycobacterium tuberculosis counteracts this process via HIF-1α activationGenoula, MelanieMarin Franco, Jose LuisMaio, MarianoDolotowicz, BelénFerreyra Compagnucci, Malena MaríaMilillo, María AyelénMascarau, RémiMoraña, Eduardo JoséPalmero, Domingo JuanMatteo, Mario JoséFuentes, FedericoLópez, BeatrizBarrionuevo, PaulaNeyrolles, OlivierCougoule, CélineLugo Villarino, GeanncarloVérollet, ChristelSasiain, María del CarmenBalboa, LucianaBETA OXIDATION OF FATTY ACIDSFOAMY MACROPHAGESHYPOXIA INDUCIBLE FACTOR 1ALPHAINTERLEUKIN 4IMMUNOMETABOLISMMYCOBACTERIUM TUBERCULOSISSIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 6https://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3The ability of Mycobacterium tuberculosis (Mtb) to persist inside host cells relies on metabolic adaptation, like the accumulation of lipid bodies (LBs) in the so-called foamy macrophages (FM), which are favorable to Mtb. The activation state of macrophages is tightly associated to different metabolic pathways, such as lipid metabolism, but whether differentiation towards FM differs between the macrophage activation profiles remains unclear. Here, we aimed to elucidate whether distinct macrophage activation states exposed to a tuberculosis-associated microenvironment or directly infected with Mtb can form FM. We showed that the triggering of signal transducer and activator of transcription 6 (STAT6) in interleukin (IL)-4-activated human macrophages (M(IL-4)) prevents FM formation induced by pleural effusion from patients with tuberculosis. In these cells, LBs are disrupted by lipolysis, and the released fatty acids enter the β-oxidation (FAO) pathway fueling the generation of ATP in mitochondria. Accordingly, murine alveolar macrophages, which exhibit a predominant FAO metabolism, are less prone to become FM than bone marrow derived-macrophages. Interestingly, direct infection of M(IL-4) macrophages with Mtb results in the establishment of aerobic glycolytic pathway and FM formation, which could be prevented by FAO activation or inhibition of the hypoxia-inducible factor 1-alpha (HIF-1α)-induced glycolytic pathway. In conclusion, our results demonstrate that Mtb has a remarkable capacity to induce FM formation through the rewiring of metabolic pathways in human macrophages, including the STAT6-driven alternatively activated program. This study provides key insights into macrophage metabolism and pathogen subversion strategies.Fil: Genoula, Melanie. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Centre National de la Recherche Scientifique; Francia. International Associated Laboratory; ArgentinaFil: Marin Franco, Jose Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Centre National de la Recherche Scientifique; Francia. International Associated Laboratory; ArgentinaFil: Maio, Mariano. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Dolotowicz, Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Ferreyra Compagnucci, Malena María. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Milillo, María Ayelén. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Mascarau, Rémi. Université de Toulouse; Francia. Centre National de la Recherche Scientifique; FranciaFil: Moraña, Eduardo José. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; ArgentinaFil: Palmero, Domingo Juan. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; ArgentinaFil: Matteo, Mario José. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Tisioneumonología "raúl F. Vaccarezza".; ArgentinaFil: Fuentes, Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: López, Beatriz. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud "Dr. C. G. Malbrán"; ArgentinaFil: Barrionuevo, Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Neyrolles, Olivier. International Associated Laboratory; Argentina. Université de Toulouse; Francia. Centre National de la Recherche Scientifique; FranciaFil: Cougoule, Céline. Centre National de la Recherche Scientifique; Francia. Université de Toulouse; Francia. International Associated Laboratory; ArgentinaFil: Lugo Villarino, Geanncarlo. Centre National de la Recherche Scientifique; Francia. Université de Toulouse; Francia. International Associated Laboratory; ArgentinaFil: Vérollet, Christel. Centre National de la Recherche Scientifique; Francia. International Associated Laboratory; Argentina. Université de Toulouse; FranciaFil: Sasiain, María del Carmen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Centre National de la Recherche Scientifique; Francia. International Associated Laboratory; ArgentinaFil: Balboa, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Centre National de la Recherche Scientifique; Francia. International Associated Laboratory; ArgentinaPublic Library of Science2020-10info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/117595Genoula, Melanie; Marin Franco, Jose Luis; Maio, Mariano; Dolotowicz, Belén; Ferreyra Compagnucci, Malena María; et al.; Fatty acid oxidation of alternatively activated macrophages prevents foam cell formation, but Mycobacterium tuberculosis counteracts this process via HIF-1α activation; Public Library of Science; Plos Pathogens; 16; 10; 10-2020; 1-281553-7366CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1371/journal.ppat.1008929info:eu-repo/semantics/altIdentifier/url/https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1008929info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:33:30Zoai:ri.conicet.gov.ar:11336/117595instacron: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:34982025-10-22 11:33:30.653CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
| dc.title.none.fl_str_mv |
Fatty acid oxidation of alternatively activated macrophages prevents foam cell formation, but Mycobacterium tuberculosis counteracts this process via HIF-1α activation |
| title |
Fatty acid oxidation of alternatively activated macrophages prevents foam cell formation, but Mycobacterium tuberculosis counteracts this process via HIF-1α activation |
| spellingShingle |
Fatty acid oxidation of alternatively activated macrophages prevents foam cell formation, but Mycobacterium tuberculosis counteracts this process via HIF-1α activation Genoula, Melanie BETA OXIDATION OF FATTY ACIDS FOAMY MACROPHAGES HYPOXIA INDUCIBLE FACTOR 1ALPHA INTERLEUKIN 4 IMMUNOMETABOLISM MYCOBACTERIUM TUBERCULOSIS SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 6 |
| title_short |
Fatty acid oxidation of alternatively activated macrophages prevents foam cell formation, but Mycobacterium tuberculosis counteracts this process via HIF-1α activation |
| title_full |
Fatty acid oxidation of alternatively activated macrophages prevents foam cell formation, but Mycobacterium tuberculosis counteracts this process via HIF-1α activation |
| title_fullStr |
Fatty acid oxidation of alternatively activated macrophages prevents foam cell formation, but Mycobacterium tuberculosis counteracts this process via HIF-1α activation |
| title_full_unstemmed |
Fatty acid oxidation of alternatively activated macrophages prevents foam cell formation, but Mycobacterium tuberculosis counteracts this process via HIF-1α activation |
| title_sort |
Fatty acid oxidation of alternatively activated macrophages prevents foam cell formation, but Mycobacterium tuberculosis counteracts this process via HIF-1α activation |
| dc.creator.none.fl_str_mv |
Genoula, Melanie Marin Franco, Jose Luis Maio, Mariano Dolotowicz, Belén Ferreyra Compagnucci, Malena María Milillo, María Ayelén Mascarau, Rémi Moraña, Eduardo José Palmero, Domingo Juan Matteo, Mario José Fuentes, Federico López, Beatriz Barrionuevo, Paula Neyrolles, Olivier Cougoule, Céline Lugo Villarino, Geanncarlo Vérollet, Christel Sasiain, María del Carmen Balboa, Luciana |
| author |
Genoula, Melanie |
| author_facet |
Genoula, Melanie Marin Franco, Jose Luis Maio, Mariano Dolotowicz, Belén Ferreyra Compagnucci, Malena María Milillo, María Ayelén Mascarau, Rémi Moraña, Eduardo José Palmero, Domingo Juan Matteo, Mario José Fuentes, Federico López, Beatriz Barrionuevo, Paula Neyrolles, Olivier Cougoule, Céline Lugo Villarino, Geanncarlo Vérollet, Christel Sasiain, María del Carmen Balboa, Luciana |
| author_role |
author |
| author2 |
Marin Franco, Jose Luis Maio, Mariano Dolotowicz, Belén Ferreyra Compagnucci, Malena María Milillo, María Ayelén Mascarau, Rémi Moraña, Eduardo José Palmero, Domingo Juan Matteo, Mario José Fuentes, Federico López, Beatriz Barrionuevo, Paula Neyrolles, Olivier Cougoule, Céline Lugo Villarino, Geanncarlo Vérollet, Christel Sasiain, María del Carmen Balboa, Luciana |
| author2_role |
author author author author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
BETA OXIDATION OF FATTY ACIDS FOAMY MACROPHAGES HYPOXIA INDUCIBLE FACTOR 1ALPHA INTERLEUKIN 4 IMMUNOMETABOLISM MYCOBACTERIUM TUBERCULOSIS SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 6 |
| topic |
BETA OXIDATION OF FATTY ACIDS FOAMY MACROPHAGES HYPOXIA INDUCIBLE FACTOR 1ALPHA INTERLEUKIN 4 IMMUNOMETABOLISM MYCOBACTERIUM TUBERCULOSIS SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 6 |
| purl_subject.fl_str_mv |
https://purl.org/becyt/ford/3.1 https://purl.org/becyt/ford/3 |
| dc.description.none.fl_txt_mv |
The ability of Mycobacterium tuberculosis (Mtb) to persist inside host cells relies on metabolic adaptation, like the accumulation of lipid bodies (LBs) in the so-called foamy macrophages (FM), which are favorable to Mtb. The activation state of macrophages is tightly associated to different metabolic pathways, such as lipid metabolism, but whether differentiation towards FM differs between the macrophage activation profiles remains unclear. Here, we aimed to elucidate whether distinct macrophage activation states exposed to a tuberculosis-associated microenvironment or directly infected with Mtb can form FM. We showed that the triggering of signal transducer and activator of transcription 6 (STAT6) in interleukin (IL)-4-activated human macrophages (M(IL-4)) prevents FM formation induced by pleural effusion from patients with tuberculosis. In these cells, LBs are disrupted by lipolysis, and the released fatty acids enter the β-oxidation (FAO) pathway fueling the generation of ATP in mitochondria. Accordingly, murine alveolar macrophages, which exhibit a predominant FAO metabolism, are less prone to become FM than bone marrow derived-macrophages. Interestingly, direct infection of M(IL-4) macrophages with Mtb results in the establishment of aerobic glycolytic pathway and FM formation, which could be prevented by FAO activation or inhibition of the hypoxia-inducible factor 1-alpha (HIF-1α)-induced glycolytic pathway. In conclusion, our results demonstrate that Mtb has a remarkable capacity to induce FM formation through the rewiring of metabolic pathways in human macrophages, including the STAT6-driven alternatively activated program. This study provides key insights into macrophage metabolism and pathogen subversion strategies. Fil: Genoula, Melanie. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Centre National de la Recherche Scientifique; Francia. International Associated Laboratory; Argentina Fil: Marin Franco, Jose Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Centre National de la Recherche Scientifique; Francia. International Associated Laboratory; Argentina Fil: Maio, Mariano. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina Fil: Dolotowicz, Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina Fil: Ferreyra Compagnucci, Malena María. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina Fil: Milillo, María Ayelén. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina Fil: Mascarau, Rémi. Université de Toulouse; Francia. Centre National de la Recherche Scientifique; Francia Fil: Moraña, Eduardo José. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; Argentina Fil: Palmero, Domingo Juan. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; Argentina Fil: Matteo, Mario José. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Tisioneumonología "raúl F. Vaccarezza".; Argentina Fil: Fuentes, Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina Fil: López, Beatriz. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud "Dr. C. G. Malbrán"; Argentina Fil: Barrionuevo, Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina Fil: Neyrolles, Olivier. International Associated Laboratory; Argentina. Université de Toulouse; Francia. Centre National de la Recherche Scientifique; Francia Fil: Cougoule, Céline. Centre National de la Recherche Scientifique; Francia. Université de Toulouse; Francia. International Associated Laboratory; Argentina Fil: Lugo Villarino, Geanncarlo. Centre National de la Recherche Scientifique; Francia. Université de Toulouse; Francia. International Associated Laboratory; Argentina Fil: Vérollet, Christel. Centre National de la Recherche Scientifique; Francia. International Associated Laboratory; Argentina. Université de Toulouse; Francia Fil: Sasiain, María del Carmen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Centre National de la Recherche Scientifique; Francia. International Associated Laboratory; Argentina Fil: Balboa, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Centre National de la Recherche Scientifique; Francia. International Associated Laboratory; Argentina |
| description |
The ability of Mycobacterium tuberculosis (Mtb) to persist inside host cells relies on metabolic adaptation, like the accumulation of lipid bodies (LBs) in the so-called foamy macrophages (FM), which are favorable to Mtb. The activation state of macrophages is tightly associated to different metabolic pathways, such as lipid metabolism, but whether differentiation towards FM differs between the macrophage activation profiles remains unclear. Here, we aimed to elucidate whether distinct macrophage activation states exposed to a tuberculosis-associated microenvironment or directly infected with Mtb can form FM. We showed that the triggering of signal transducer and activator of transcription 6 (STAT6) in interleukin (IL)-4-activated human macrophages (M(IL-4)) prevents FM formation induced by pleural effusion from patients with tuberculosis. In these cells, LBs are disrupted by lipolysis, and the released fatty acids enter the β-oxidation (FAO) pathway fueling the generation of ATP in mitochondria. Accordingly, murine alveolar macrophages, which exhibit a predominant FAO metabolism, are less prone to become FM than bone marrow derived-macrophages. Interestingly, direct infection of M(IL-4) macrophages with Mtb results in the establishment of aerobic glycolytic pathway and FM formation, which could be prevented by FAO activation or inhibition of the hypoxia-inducible factor 1-alpha (HIF-1α)-induced glycolytic pathway. In conclusion, our results demonstrate that Mtb has a remarkable capacity to induce FM formation through the rewiring of metabolic pathways in human macrophages, including the STAT6-driven alternatively activated program. This study provides key insights into macrophage metabolism and pathogen subversion strategies. |
| publishDate |
2020 |
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2020-10 |
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article |
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publishedVersion |
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http://hdl.handle.net/11336/117595 Genoula, Melanie; Marin Franco, Jose Luis; Maio, Mariano; Dolotowicz, Belén; Ferreyra Compagnucci, Malena María; et al.; Fatty acid oxidation of alternatively activated macrophages prevents foam cell formation, but Mycobacterium tuberculosis counteracts this process via HIF-1α activation; Public Library of Science; Plos Pathogens; 16; 10; 10-2020; 1-28 1553-7366 CONICET Digital CONICET |
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http://hdl.handle.net/11336/117595 |
| identifier_str_mv |
Genoula, Melanie; Marin Franco, Jose Luis; Maio, Mariano; Dolotowicz, Belén; Ferreyra Compagnucci, Malena María; et al.; Fatty acid oxidation of alternatively activated macrophages prevents foam cell formation, but Mycobacterium tuberculosis counteracts this process via HIF-1α activation; Public Library of Science; Plos Pathogens; 16; 10; 10-2020; 1-28 1553-7366 CONICET Digital CONICET |
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eng |
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