The Cholinergic System Contributes to the Immunopathological Progression of Experimental Pulmonary Tuberculosis

Autores
Islas Weinstein, Leon; Marquina Castillo, Brenda; Mata Espinosa, Dulce; Paredes González, Iris S.; Chávez, Jaime; Balboa, Luciana; Marin Franco, Jose Luis; Guerrero Romero, Daniel; Barrios Payan, Jorge Alberto; Hernandez Pando, Rogelio
Año de publicación
2021
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The cholinergic system is present in both bacteria and mammals and regulates inflammation during bacterial respiratory infections through neuronal and non-neuronal production of acetylcholine (ACh) and its receptors. However, the presence of this system during the immunopathogenesis of pulmonary tuberculosis (TB) in vivo and in its causative agent Mycobacterium tuberculosis (Mtb) has not been studied. Therefore, we used an experimental model of progressive pulmonary TB in BALB/c mice to quantify pulmonary ACh using high-performance liquid chromatography during the course of the disease. In addition, we performed immunohistochemistry in lung tissue to determine the cellular expression of cholinergic system components, and then administered nicotinic receptor (nAChR) antagonists to validate their effect on lung bacterial burden, inflammation, and pro-inflammatory cytokines. Finally, we subjected Mtb cultures to colorimetric analysis to reveal the production of ACh and the effect of ACh and nAChR antagonists on Mtb growth. Our results show high concentrations of ACh and expression of its synthesizing enzyme choline acetyltransferase (ChAT) during early infection in lung epithelial cells and macrophages. During late progressive TB, lung ACh upregulation was even higher and coincided with ChAT and α7 nAChR subunit expression in immune cells. Moreover, the administration of nAChR antagonists increased pro-inflammatory cytokines, reduced bacillary loads and synergized with antibiotic therapy in multidrug resistant TB. Finally, in vitro studies revealed that the bacteria is capable of producing nanomolar concentrations of ACh in liquid culture. In addition, the administration of ACh and nicotinic antagonists to Mtb cultures induced or inhibited bacterial proliferation, respectively. These results suggest that Mtb possesses a cholinergic system and upregulates the lung non-neuronal cholinergic system, particularly during late progressive TB. The upregulation of the cholinergic system during infection could aid both bacterial growth and immunomodulation within the lung to favor disease progression. Furthermore, the therapeutic efficacy of modulating this system suggests that it could be a target for treating the disease.
Fil: Islas Weinstein, Leon. Instituto Nacional de Ciencias Médicas y Nutrición Sz; México
Fil: Marquina Castillo, Brenda. Instituto Nacional de Ciencias Médicas y Nutrición Sz; México
Fil: Mata Espinosa, Dulce. Instituto Nacional de Ciencias Médicas y Nutrición Sz; México
Fil: Paredes González, Iris S.. Instituto Nacional de Ciencias Médicas y Nutrición Sz; México
Fil: Chávez, Jaime. Instituto Nacional de Ciencias Médicas y Nutrición Sz; México
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
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
Fil: Guerrero Romero, Daniel. Instituto Nacional de Ciencias Médicas y Nutrición Sz; México
Fil: Barrios Payan, Jorge Alberto. Instituto Nacional de Ciencias Médicas y Nutrición Sz; México
Fil: Hernandez Pando, Rogelio. Instituto Nacional de Ciencias Médicas y Nutrición Sz; México
Materia
ACETYLCHOLINE
CHOLINERGIC SYSTEM
MYCOBACTERIUM TUBERCULOSIS
TUBERCULOSIS
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/156682

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network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling The Cholinergic System Contributes to the Immunopathological Progression of Experimental Pulmonary TuberculosisIslas Weinstein, LeonMarquina Castillo, BrendaMata Espinosa, DulceParedes González, Iris S.Chávez, JaimeBalboa, LucianaMarin Franco, Jose LuisGuerrero Romero, DanielBarrios Payan, Jorge AlbertoHernandez Pando, RogelioACETYLCHOLINECHOLINERGIC SYSTEMMYCOBACTERIUM TUBERCULOSISTUBERCULOSIShttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3The cholinergic system is present in both bacteria and mammals and regulates inflammation during bacterial respiratory infections through neuronal and non-neuronal production of acetylcholine (ACh) and its receptors. However, the presence of this system during the immunopathogenesis of pulmonary tuberculosis (TB) in vivo and in its causative agent Mycobacterium tuberculosis (Mtb) has not been studied. Therefore, we used an experimental model of progressive pulmonary TB in BALB/c mice to quantify pulmonary ACh using high-performance liquid chromatography during the course of the disease. In addition, we performed immunohistochemistry in lung tissue to determine the cellular expression of cholinergic system components, and then administered nicotinic receptor (nAChR) antagonists to validate their effect on lung bacterial burden, inflammation, and pro-inflammatory cytokines. Finally, we subjected Mtb cultures to colorimetric analysis to reveal the production of ACh and the effect of ACh and nAChR antagonists on Mtb growth. Our results show high concentrations of ACh and expression of its synthesizing enzyme choline acetyltransferase (ChAT) during early infection in lung epithelial cells and macrophages. During late progressive TB, lung ACh upregulation was even higher and coincided with ChAT and α7 nAChR subunit expression in immune cells. Moreover, the administration of nAChR antagonists increased pro-inflammatory cytokines, reduced bacillary loads and synergized with antibiotic therapy in multidrug resistant TB. Finally, in vitro studies revealed that the bacteria is capable of producing nanomolar concentrations of ACh in liquid culture. In addition, the administration of ACh and nicotinic antagonists to Mtb cultures induced or inhibited bacterial proliferation, respectively. These results suggest that Mtb possesses a cholinergic system and upregulates the lung non-neuronal cholinergic system, particularly during late progressive TB. The upregulation of the cholinergic system during infection could aid both bacterial growth and immunomodulation within the lung to favor disease progression. Furthermore, the therapeutic efficacy of modulating this system suggests that it could be a target for treating the disease.Fil: Islas Weinstein, Leon. Instituto Nacional de Ciencias Médicas y Nutrición Sz; MéxicoFil: Marquina Castillo, Brenda. Instituto Nacional de Ciencias Médicas y Nutrición Sz; MéxicoFil: Mata Espinosa, Dulce. Instituto Nacional de Ciencias Médicas y Nutrición Sz; MéxicoFil: Paredes González, Iris S.. Instituto Nacional de Ciencias Médicas y Nutrición Sz; MéxicoFil: Chávez, Jaime. Instituto Nacional de Ciencias Médicas y Nutrición Sz; MéxicoFil: Balboa, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; 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; ArgentinaFil: Guerrero Romero, Daniel. Instituto Nacional de Ciencias Médicas y Nutrición Sz; MéxicoFil: Barrios Payan, Jorge Alberto. Instituto Nacional de Ciencias Médicas y Nutrición Sz; MéxicoFil: Hernandez Pando, Rogelio. Instituto Nacional de Ciencias Médicas y Nutrición Sz; MéxicoFrontiers Research Foundation2021-02info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/156682Islas Weinstein, Leon; Marquina Castillo, Brenda; Mata Espinosa, Dulce; Paredes González, Iris S.; Chávez, Jaime; et al.; The Cholinergic System Contributes to the Immunopathological Progression of Experimental Pulmonary Tuberculosis; Frontiers Research Foundation; Frontiers in immunology; 11; 2-2021; 1-141664-3224CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.frontiersin.org/articles/10.3389/fimmu.2020.581911/fullinfo:eu-repo/semantics/altIdentifier/doi/10.3389/fimmu.2020.581911info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:57:01Zoai:ri.conicet.gov.ar:11336/156682instacron: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:34982025-09-03 09:57:02.032CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv The Cholinergic System Contributes to the Immunopathological Progression of Experimental Pulmonary Tuberculosis
title The Cholinergic System Contributes to the Immunopathological Progression of Experimental Pulmonary Tuberculosis
spellingShingle The Cholinergic System Contributes to the Immunopathological Progression of Experimental Pulmonary Tuberculosis
Islas Weinstein, Leon
ACETYLCHOLINE
CHOLINERGIC SYSTEM
MYCOBACTERIUM TUBERCULOSIS
TUBERCULOSIS
title_short The Cholinergic System Contributes to the Immunopathological Progression of Experimental Pulmonary Tuberculosis
title_full The Cholinergic System Contributes to the Immunopathological Progression of Experimental Pulmonary Tuberculosis
title_fullStr The Cholinergic System Contributes to the Immunopathological Progression of Experimental Pulmonary Tuberculosis
title_full_unstemmed The Cholinergic System Contributes to the Immunopathological Progression of Experimental Pulmonary Tuberculosis
title_sort The Cholinergic System Contributes to the Immunopathological Progression of Experimental Pulmonary Tuberculosis
dc.creator.none.fl_str_mv Islas Weinstein, Leon
Marquina Castillo, Brenda
Mata Espinosa, Dulce
Paredes González, Iris S.
Chávez, Jaime
Balboa, Luciana
Marin Franco, Jose Luis
Guerrero Romero, Daniel
Barrios Payan, Jorge Alberto
Hernandez Pando, Rogelio
author Islas Weinstein, Leon
author_facet Islas Weinstein, Leon
Marquina Castillo, Brenda
Mata Espinosa, Dulce
Paredes González, Iris S.
Chávez, Jaime
Balboa, Luciana
Marin Franco, Jose Luis
Guerrero Romero, Daniel
Barrios Payan, Jorge Alberto
Hernandez Pando, Rogelio
author_role author
author2 Marquina Castillo, Brenda
Mata Espinosa, Dulce
Paredes González, Iris S.
Chávez, Jaime
Balboa, Luciana
Marin Franco, Jose Luis
Guerrero Romero, Daniel
Barrios Payan, Jorge Alberto
Hernandez Pando, Rogelio
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv ACETYLCHOLINE
CHOLINERGIC SYSTEM
MYCOBACTERIUM TUBERCULOSIS
TUBERCULOSIS
topic ACETYLCHOLINE
CHOLINERGIC SYSTEM
MYCOBACTERIUM TUBERCULOSIS
TUBERCULOSIS
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 cholinergic system is present in both bacteria and mammals and regulates inflammation during bacterial respiratory infections through neuronal and non-neuronal production of acetylcholine (ACh) and its receptors. However, the presence of this system during the immunopathogenesis of pulmonary tuberculosis (TB) in vivo and in its causative agent Mycobacterium tuberculosis (Mtb) has not been studied. Therefore, we used an experimental model of progressive pulmonary TB in BALB/c mice to quantify pulmonary ACh using high-performance liquid chromatography during the course of the disease. In addition, we performed immunohistochemistry in lung tissue to determine the cellular expression of cholinergic system components, and then administered nicotinic receptor (nAChR) antagonists to validate their effect on lung bacterial burden, inflammation, and pro-inflammatory cytokines. Finally, we subjected Mtb cultures to colorimetric analysis to reveal the production of ACh and the effect of ACh and nAChR antagonists on Mtb growth. Our results show high concentrations of ACh and expression of its synthesizing enzyme choline acetyltransferase (ChAT) during early infection in lung epithelial cells and macrophages. During late progressive TB, lung ACh upregulation was even higher and coincided with ChAT and α7 nAChR subunit expression in immune cells. Moreover, the administration of nAChR antagonists increased pro-inflammatory cytokines, reduced bacillary loads and synergized with antibiotic therapy in multidrug resistant TB. Finally, in vitro studies revealed that the bacteria is capable of producing nanomolar concentrations of ACh in liquid culture. In addition, the administration of ACh and nicotinic antagonists to Mtb cultures induced or inhibited bacterial proliferation, respectively. These results suggest that Mtb possesses a cholinergic system and upregulates the lung non-neuronal cholinergic system, particularly during late progressive TB. The upregulation of the cholinergic system during infection could aid both bacterial growth and immunomodulation within the lung to favor disease progression. Furthermore, the therapeutic efficacy of modulating this system suggests that it could be a target for treating the disease.
Fil: Islas Weinstein, Leon. Instituto Nacional de Ciencias Médicas y Nutrición Sz; México
Fil: Marquina Castillo, Brenda. Instituto Nacional de Ciencias Médicas y Nutrición Sz; México
Fil: Mata Espinosa, Dulce. Instituto Nacional de Ciencias Médicas y Nutrición Sz; México
Fil: Paredes González, Iris S.. Instituto Nacional de Ciencias Médicas y Nutrición Sz; México
Fil: Chávez, Jaime. Instituto Nacional de Ciencias Médicas y Nutrición Sz; México
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
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
Fil: Guerrero Romero, Daniel. Instituto Nacional de Ciencias Médicas y Nutrición Sz; México
Fil: Barrios Payan, Jorge Alberto. Instituto Nacional de Ciencias Médicas y Nutrición Sz; México
Fil: Hernandez Pando, Rogelio. Instituto Nacional de Ciencias Médicas y Nutrición Sz; México
description The cholinergic system is present in both bacteria and mammals and regulates inflammation during bacterial respiratory infections through neuronal and non-neuronal production of acetylcholine (ACh) and its receptors. However, the presence of this system during the immunopathogenesis of pulmonary tuberculosis (TB) in vivo and in its causative agent Mycobacterium tuberculosis (Mtb) has not been studied. Therefore, we used an experimental model of progressive pulmonary TB in BALB/c mice to quantify pulmonary ACh using high-performance liquid chromatography during the course of the disease. In addition, we performed immunohistochemistry in lung tissue to determine the cellular expression of cholinergic system components, and then administered nicotinic receptor (nAChR) antagonists to validate their effect on lung bacterial burden, inflammation, and pro-inflammatory cytokines. Finally, we subjected Mtb cultures to colorimetric analysis to reveal the production of ACh and the effect of ACh and nAChR antagonists on Mtb growth. Our results show high concentrations of ACh and expression of its synthesizing enzyme choline acetyltransferase (ChAT) during early infection in lung epithelial cells and macrophages. During late progressive TB, lung ACh upregulation was even higher and coincided with ChAT and α7 nAChR subunit expression in immune cells. Moreover, the administration of nAChR antagonists increased pro-inflammatory cytokines, reduced bacillary loads and synergized with antibiotic therapy in multidrug resistant TB. Finally, in vitro studies revealed that the bacteria is capable of producing nanomolar concentrations of ACh in liquid culture. In addition, the administration of ACh and nicotinic antagonists to Mtb cultures induced or inhibited bacterial proliferation, respectively. These results suggest that Mtb possesses a cholinergic system and upregulates the lung non-neuronal cholinergic system, particularly during late progressive TB. The upregulation of the cholinergic system during infection could aid both bacterial growth and immunomodulation within the lung to favor disease progression. Furthermore, the therapeutic efficacy of modulating this system suggests that it could be a target for treating the disease.
publishDate 2021
dc.date.none.fl_str_mv 2021-02
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
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/156682
Islas Weinstein, Leon; Marquina Castillo, Brenda; Mata Espinosa, Dulce; Paredes González, Iris S.; Chávez, Jaime; et al.; The Cholinergic System Contributes to the Immunopathological Progression of Experimental Pulmonary Tuberculosis; Frontiers Research Foundation; Frontiers in immunology; 11; 2-2021; 1-14
1664-3224
CONICET Digital
CONICET
url http://hdl.handle.net/11336/156682
identifier_str_mv Islas Weinstein, Leon; Marquina Castillo, Brenda; Mata Espinosa, Dulce; Paredes González, Iris S.; Chávez, Jaime; et al.; The Cholinergic System Contributes to the Immunopathological Progression of Experimental Pulmonary Tuberculosis; Frontiers Research Foundation; Frontiers in immunology; 11; 2-2021; 1-14
1664-3224
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.frontiersin.org/articles/10.3389/fimmu.2020.581911/full
info:eu-repo/semantics/altIdentifier/doi/10.3389/fimmu.2020.581911
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Frontiers Research Foundation
publisher.none.fl_str_mv Frontiers Research Foundation
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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