publishedVersion
Formation of foamy macrophages by tuberculous pleural effusions is triggered by the interleukin-10/Signal transducer and activator of transcription 3 axis through ACAT upregulation
Autor
Genoula, Melanie
Marín Franco, José Luis
Dupont, Maeva
Kviatcovsky, Denise
Milillo, Ayelén
Schierloh, Pablo
Moraña, Eduardo Jose
Poggi, Susana
Palmero, Domingo
Mata-Espinosa, Dulce
González-Domínguez, Erika
León Contreras, Juan Carlos
Barrionuevo, Paula
Rearte, Bárbara
Córdoba Moreno, Marlina Olyissa
Fontanals, Adriana
Crotta Asis, Agostina
Gago, Gabriela
Cougoule, Céline
Neyrolles, Olivier
Maridonneau-Parini, Isabelle
Sánchez-Torres, Carmen
Hernández-Pando, Rogelio
Vérollet, Christel
Lugo-Villarino, Geanncarlo
Sasiain, María del Carmen
Balboa, Luciana
Institución
Resumen
The ability of Mycobacterium tuberculosis (Mtb) to persist in its human host relies on numerous immune evasion strategies, such as the deregulation of the lipid metabolism leading to the formation of foamy macrophages (FM). Yet, the specific host factors leading to the foamy phenotype of Mtb-infected macrophages remain unknown. Herein, we aimed to address whether host cytokines contribute to FM formation in the context of Mtb infection. Our approach is based on the use of an acellular fraction of tuberculous pleural effusions (TB-PE) as a physiological source of local factors released during Mtb infection. We found that TB-PE induced FM differentiation as observed by the increase in lipid bodies, intracellular cholesterol, and expression of the scavenger receptor CD36, as well as the enzyme acyl CoA:cholesterol acyl transferase (ACAT). Importantly, interleukin-10 (IL-10) depletion from TB-PE prevented the augmentation of all these parameters. Moreover, we observed a positive correlation between the levels of IL-10 and the number of lipid-laden CD14+ cells among the pleural cells in TB patients, demonstrating that FM differentiation occurs within the pleural environment. Downstream of IL-10 signaling, we noticed that the transcription factor signal transducer and activator of transcription 3 was activated by TB-PE, and its chemical inhibition prevented the accumulation of lipid bodies and ACAT expression in macrophages. In terms of the host immune response, TB-PE-treated macrophages displayed immunosuppressive properties and bore higher bacillary loads. Finally, we confirmed our results using bone marrow-derived macrophage from IL-10−/− mice demonstrating that IL-10 deficiency partially prevented foamy phenotype induction after Mtb lipids exposure. In conclusion, our results evidence a role of IL-10 in promoting the differentiation of FM in the context of Mtb infection, contributing to our understanding of how alterations of the host metabolic factors may favor pathogen persistence. Fil: Genoula, Melanie. Academia Nacional de Medicina. Instituto de Medicina Experimental (IMEX-CONICET). Laboratorio de Inmunología de Enfermedades Respiratorias; Argentina. Fil: Genoula, Melanie. International Associated Laboratory (LIA) CNRS IM-TB/HIV (1167); France. Fil: Genoula, Melanie. International Associated Laboratory (LIA) CNRS IM-TB/HIV (1167); Argentina. Fil: Marín Franco, José Luis. Academia Nacional de Medicina. Instituto de Medicina Experimental (IMEX-CONICET). Laboratorio de Inmunología de Enfermedades Respiratorias; Argentina. Fil: Marín Franco, José Luis. International Associated Laboratory (LIA) CNRS IM-TB/HIV (1167); France. Fil: Marín Franco, José Luis. International Associated Laboratory (LIA) CNRS IM-TB/HIV (1167); Argentina. Fil: Dupont, Maeva. International Associated Laboratory (LIA) CNRS IM-TB/HIV (1167); France. Fil: Dupont, Maeva. International Associated Laboratory (LIA) CNRS IM-TB/HIV (1167); Argentina. Fil: Dupont, Maeva. Université de Toulouse. Institut de Pharmacologie et de Biologie Structurale (CNR, UPS); France. Fil: Kviatcovsky, Denise. Academia Nacional de Medicina. Instituto de Medicina Experimental (IMEX-CONICET). Laboratorio de Inmunología de Enfermedades Respiratorias; Argentina. Fil: Kviatcovsky, Denise. International Associated Laboratory (LIA) CNRS IM-TB/HIV (1167); France. Fil: Kviatcovsky, Denise. International Associated Laboratory (LIA) CNRS IM-TB/HIV (1167); Argentina. Fil: Milillo, Ayelén. Academia Nacional de Medicina. Instituto de Medicina Experimental (IMEX-CONICET). Laboratorio de Fisiología de los Procesos Inflamatorios; Argentina. Fil: Schierloh, Pablo. Academia Nacional de Medicina. Instituto de Medicina Experimental (IMEX-CONICET). Laboratorio de Inmunología de Enfermedades Respiratorias; Argentina. Fil: Schierloh, Pablo. International Associated Laboratory (LIA) CNRS IM-TB/HIV (1167); France. Fil: Schierloh, Pablo. International Associated Laboratory (LIA) CNRS IM-TB/HIV (1167); Argentina. Fil: Moraña, Eduardo Jose. Hospital de Infecciosas Dr. F. J. Muñiz. Instituto Prof. Dr. Raúl Vaccarezza; Argentina. Fil: Poggi, Susana. Hospital de Infecciosas Dr. F. J. Muñiz. Instituto Prof. Dr. Raúl Vaccarezza; Argentina. Fil: Palmero, Domingo. Hospital de Infecciosas Dr. F. J. Muñiz. Instituto Prof. Dr. Raúl Vaccarezza; Argentina. Fil: Mata-Espinosa, Dulce. Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. Departamento de Patología. Sección de Patología Experimental; Mexico. Fil: González-Domínguez, Erika. Instituto Politécnico Nacional. Centro de Investigación y de Estudios Avanzados. Departamento de Biomedicina Molecular; Mexico. Fil: León Contreras, Juan Carlos. Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. Departamento de Patología. Sección de Patología Experimental; Mexico. Fil: Barrionuevo, Paula. Academia Nacional de Medicina. Instituto de Medicina Experimental (IMEX-CONICET). Laboratorio de Fisiología de los Procesos Inflamatorios; Argentina. Fil: Rearte, Bárbara. Academia Nacional de Medicina. Instituto de Medicina Experimental (IMEX-CONICET). Laboratorio de Fisiología de los Procesos Inflamatorios; Argentina. Fil: Córdoba Moreno, Marlina Olyissa. Academia Nacional de Medicina. Instituto de Medicina Experimental (IMEX-CONICET). Laboratorio de Fisiología de los Procesos Inflamatorios; Argentina. Fil: Fontanals, Adriana. Fundación Instituto Leloir; Argentina. Fil: Crotta Asis, Agostina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario (IBR-CONICET). Laboratorio de Fisiología y Genética de Actinomycetes; Argentina. Fil: Gago, Gabriela. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario (IBR-CONICET). Laboratorio de Fisiología y Genética de Actinomycetes; Argentina. Fil: Cougoule, Céline. International Associated Laboratory (LIA) CNRS IM-TB/HIV (1167); France. Fil: Cougoule, Céline. International Associated Laboratory (LIA) CNRS IM-TB/HIV (1167); Argentina. Fil: Cougoule, Céline. Université de Toulouse. Institut de Pharmacologie et de Biologie Structurale (CNR, UPS); France. Fil: Neyrolles, Olivier. International Associated Laboratory (LIA) CNRS IM-TB/HIV (1167); France. Fil: Neyrolles, Olivier. International Associated Laboratory (LIA) CNRS IM-TB/HIV (1167); Argentina. Fil: Neyrolles, Olivier. Université de Toulouse. Institut de Pharmacologie et de Biologie Structurale (CNR, UPS); France. Fil: Maridonneau-Parini, Isabelle. International Associated Laboratory (LIA) CNRS IM-TB/HIV (1167); France. Fil: Maridonneau-Parini, Isabelle. International Associated Laboratory (LIA) CNRS IM-TB/HIV (1167); Argentina. Fil: Maridonneau-Parini, Isabelle. Université de Toulouse. Institut de Pharmacologie et de Biologie Structurale (CNR, UPS); France. Fil: Sánchez-Torres, Carmen. Instituto Politécnico Nacional. Centro de Investigación y de Estudios Avanzados. Departamento de Biomedicina Molecular; Mexico. Fil: Hernández-Pando, Rogelio. Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. Departamento de Patología. Sección de Patología Experimental; Mexico. Fil: Vérollet, Christel. International Associated Laboratory (LIA) CNRS IM-TB/HIV (1167); France. Fil: Vérollet, Christel. International Associated Laboratory (LIA) CNRS IM-TB/HIV (1167); Argentina. Fil: Vérollet, Christel. Université de Toulouse. Institut de Pharmacologie et de Biologie Structurale (CNR, UPS); France. Fil: Lugo-Villarino, Geanncarlo. International Associated Laboratory (LIA) CNRS IM-TB/HIV (1167); France. Fil: Lugo-Villarino, Geanncarlo. International Associated Laboratory (LIA) CNRS IM-TB/HIV (1167); Argentina. Fil: Lugo-Villarino, Geanncarlo. Université de Toulouse. Institut de Pharmacologie et de Biologie Structurale (CNR, UPS); France. Fil: Sasiain, María del Carmen. Academia Nacional de Medicina. Instituto de Medicina Experimental (IMEX-CONICET). Laboratorio de Inmunología de Enfermedades Respiratorias; Argentina. Fil: Sasiain, María del Carmen. International Associated Laboratory (LIA) CNRS IM-TB/HIV (1167); France. Fil: Sasiain, María del Carmen. International Associated Laboratory (LIA) CNRS IM-TB/HIV (1167); Argentina. Fil: Balboa, Luciana. Academia Nacional de Medicina. Instituto de Medicina Experimental (IMEX-CONICET). Laboratorio de Inmunología de Enfermedades Respiratorias; Argentina. Fil: Balboa, Luciana. International Associated Laboratory (LIA) CNRS IM-TB/HIV (1167); France. Fil: Balboa, Luciana. International Associated Laboratory (LIA) CNRS IM-TB/HIV (1167); Argentina.