Pro-inflammatory monocyte profile in patients with major depressive disorder and suicide behaviour and how ketamine induces antiinflammatory M2 macrophages by NMDAR and mTOR

Autores
Nowak, Wanda; Grendas, Leandro Nicolás; Sanmarco, Liliana María; Estecho, Ivana Gisele; Arena, Ángeles Romina; Eberhardt, Natalia; Rodante, Demián Emanuel; Aoki, María Pilar; Daray, Federico Manuel; Carrera Silva, Eugenio Antonio; Errasti, Andrea Emilse
Año de publicación
2019
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Background: Depression is a highly prevalent disorder that is one of the leading causes of disability worldwide. Despite an unknown aetiology, evidence suggests that the innate and adaptive immune systems play a significant role in the development and maintenance of major depressive disorder (MDD). The non-competitive glutamatergic N-methyl-D-aspartate receptor (NMDAR) antagonist, (R,S)-ketamine (ketamine), has demonstrated rapid and robust efficacy as an antidepressant when administered at sub-anaesthetic doses. Methods: Our goal was to characterize the pro-inflammatory profile of patients with MDD by measuring proinflammatory cytokines in plasma and circulating monocyte subsets and to understand how ketamine induces an anti-inflammatory program in monocyte and macrophages in vitro and vivo. Finding: Our results show that patients with MDD without other comorbidities (N= 33) exhibited significantly higher levels of pro-inflammatory IL-12 and IL-6 in plasma and that these cytokines were associated with increased numbers of non-classical (CD11b+ CD16brightCD14neg) monocytes and increased activation state (CD40+ CD86+ ) of classical monocytes in circulation. Remarkably, we have demonstrated that sub-anaesthetic doses of ketamine programs human monocytes into M2c-like macrophages by inducing high levels of CD163 and MERTK with intermediate levels of CD64 and stimulating mTOR-associated gene expression in vitro. The NMDAR antagonist MK-801, but not the a-amino-3‑hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) antagonist, NBQX, also polarizes macrophages to an M2c-like phenotype, but this phenotype disappears upon mTOR pathway inhibition. Subanaesthetic doses (10 mg/kg) of ketamine administration in mice both promote reduction of circulating classical pro-inflammatory monocytes and increase of alternative M2 macrophage subtypes in the spleen and CNS. Interpretation: Our results suggest an anti-inflammatory property of ketamine that can skew macrophages to an M2-like phenotype, highlighting potential therapeutic implications not only for patients with MDD but also other inflammatory-based diseases.
Fil: Nowak, Wanda. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Farmacologia.; Argentina
Fil: Grendas, Leandro Nicolás. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Farmacologia.; Argentina
Fil: Sanmarco, Liliana María. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Estecho, Ivana Gisele. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Farmacologia.; Argentina
Fil: Arena, Ángeles Romina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Farmacologia.; Argentina
Fil: Eberhardt, Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Rodante, Demián Emanuel. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Farmacologia.; Argentina
Fil: Aoki, María Pilar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Daray, Federico Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Farmacologia.; Argentina
Fil: Carrera Silva, Eugenio Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Errasti, Andrea Emilse. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Farmacologia.; Argentina
Materia
DEPRESSION
IL-12
NON-CLASSICAL MONOCYTES
KETAMINE
NMDAR
mTOR PATHWAY
ANTI-INFLAMMATORY M2 MACROPHAGES
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/106773
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/106773
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Pro-inflammatory monocyte profile in patients with major depressive disorder and suicide behaviour and how ketamine induces antiinflammatory M2 macrophages by NMDAR and mTORNowak, WandaGrendas, Leandro NicolásSanmarco, Liliana MaríaEstecho, Ivana GiseleArena, Ángeles RominaEberhardt, NataliaRodante, Demián EmanuelAoki, María PilarDaray, Federico ManuelCarrera Silva, Eugenio AntonioErrasti, Andrea EmilseDEPRESSIONIL-12NON-CLASSICAL MONOCYTESKETAMINENMDARmTOR PATHWAYANTI-INFLAMMATORY M2 MACROPHAGEShttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3https://purl.org/becyt/ford/3.2https://purl.org/becyt/ford/3Background: Depression is a highly prevalent disorder that is one of the leading causes of disability worldwide. Despite an unknown aetiology, evidence suggests that the innate and adaptive immune systems play a significant role in the development and maintenance of major depressive disorder (MDD). The non-competitive glutamatergic N-methyl-D-aspartate receptor (NMDAR) antagonist, (R,S)-ketamine (ketamine), has demonstrated rapid and robust efficacy as an antidepressant when administered at sub-anaesthetic doses. Methods: Our goal was to characterize the pro-inflammatory profile of patients with MDD by measuring proinflammatory cytokines in plasma and circulating monocyte subsets and to understand how ketamine induces an anti-inflammatory program in monocyte and macrophages in vitro and vivo. Finding: Our results show that patients with MDD without other comorbidities (N= 33) exhibited significantly higher levels of pro-inflammatory IL-12 and IL-6 in plasma and that these cytokines were associated with increased numbers of non-classical (CD11b+ CD16brightCD14neg) monocytes and increased activation state (CD40+ CD86+ ) of classical monocytes in circulation. Remarkably, we have demonstrated that sub-anaesthetic doses of ketamine programs human monocytes into M2c-like macrophages by inducing high levels of CD163 and MERTK with intermediate levels of CD64 and stimulating mTOR-associated gene expression in vitro. The NMDAR antagonist MK-801, but not the a-amino-3‑hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) antagonist, NBQX, also polarizes macrophages to an M2c-like phenotype, but this phenotype disappears upon mTOR pathway inhibition. Subanaesthetic doses (10 mg/kg) of ketamine administration in mice both promote reduction of circulating classical pro-inflammatory monocytes and increase of alternative M2 macrophage subtypes in the spleen and CNS. Interpretation: Our results suggest an anti-inflammatory property of ketamine that can skew macrophages to an M2-like phenotype, highlighting potential therapeutic implications not only for patients with MDD but also other inflammatory-based diseases.Fil: Nowak, Wanda. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Farmacologia.; ArgentinaFil: Grendas, Leandro Nicolás. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Farmacologia.; ArgentinaFil: Sanmarco, Liliana María. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Estecho, Ivana Gisele. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Farmacologia.; ArgentinaFil: Arena, Ángeles Romina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Farmacologia.; ArgentinaFil: Eberhardt, Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Rodante, Demián Emanuel. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Farmacologia.; ArgentinaFil: Aoki, María Pilar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Daray, Federico Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Farmacologia.; ArgentinaFil: Carrera Silva, Eugenio Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Errasti, Andrea Emilse. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Farmacologia.; ArgentinaThe Lancet2019-12info: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/11336/106773Nowak, Wanda; Grendas, Leandro Nicolás; Sanmarco, Liliana María; Estecho, Ivana Gisele; Arena, Ángeles Romina; et al.; Pro-inflammatory monocyte profile in patients with major depressive disorder and suicide behaviour and how ketamine induces antiinflammatory M2 macrophages by NMDAR and mTOR; The Lancet; EBioMedicine; 50; 12-2019; 290-3052352-3964CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://linkinghub.elsevier.com/retrieve/pii/S2352396419307406info:eu-repo/semantics/altIdentifier/doi/10.1016/j.ebiom.2019.10.063info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T15:19:47Zoai:ri.conicet.gov.ar:11336/106773instacron: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 15:19:48.19CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Pro-inflammatory monocyte profile in patients with major depressive disorder and suicide behaviour and how ketamine induces antiinflammatory M2 macrophages by NMDAR and mTOR
title Pro-inflammatory monocyte profile in patients with major depressive disorder and suicide behaviour and how ketamine induces antiinflammatory M2 macrophages by NMDAR and mTOR
spellingShingle Pro-inflammatory monocyte profile in patients with major depressive disorder and suicide behaviour and how ketamine induces antiinflammatory M2 macrophages by NMDAR and mTOR
Nowak, Wanda
DEPRESSION
IL-12
NON-CLASSICAL MONOCYTES
KETAMINE
NMDAR
mTOR PATHWAY
ANTI-INFLAMMATORY M2 MACROPHAGES
title_short Pro-inflammatory monocyte profile in patients with major depressive disorder and suicide behaviour and how ketamine induces antiinflammatory M2 macrophages by NMDAR and mTOR
title_full Pro-inflammatory monocyte profile in patients with major depressive disorder and suicide behaviour and how ketamine induces antiinflammatory M2 macrophages by NMDAR and mTOR
title_fullStr Pro-inflammatory monocyte profile in patients with major depressive disorder and suicide behaviour and how ketamine induces antiinflammatory M2 macrophages by NMDAR and mTOR
title_full_unstemmed Pro-inflammatory monocyte profile in patients with major depressive disorder and suicide behaviour and how ketamine induces antiinflammatory M2 macrophages by NMDAR and mTOR
title_sort Pro-inflammatory monocyte profile in patients with major depressive disorder and suicide behaviour and how ketamine induces antiinflammatory M2 macrophages by NMDAR and mTOR
dc.creator.none.fl_str_mv Nowak, Wanda
Grendas, Leandro Nicolás
Sanmarco, Liliana María
Estecho, Ivana Gisele
Arena, Ángeles Romina
Eberhardt, Natalia
Rodante, Demián Emanuel
Aoki, María Pilar
Daray, Federico Manuel
Carrera Silva, Eugenio Antonio
Errasti, Andrea Emilse
author Nowak, Wanda
author_facet Nowak, Wanda
Grendas, Leandro Nicolás
Sanmarco, Liliana María
Estecho, Ivana Gisele
Arena, Ángeles Romina
Eberhardt, Natalia
Rodante, Demián Emanuel
Aoki, María Pilar
Daray, Federico Manuel
Carrera Silva, Eugenio Antonio
Errasti, Andrea Emilse
author_role author
author2 Grendas, Leandro Nicolás
Sanmarco, Liliana María
Estecho, Ivana Gisele
Arena, Ángeles Romina
Eberhardt, Natalia
Rodante, Demián Emanuel
Aoki, María Pilar
Daray, Federico Manuel
Carrera Silva, Eugenio Antonio
Errasti, Andrea Emilse
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv DEPRESSION
IL-12
NON-CLASSICAL MONOCYTES
KETAMINE
NMDAR
mTOR PATHWAY
ANTI-INFLAMMATORY M2 MACROPHAGES
topic DEPRESSION
IL-12
NON-CLASSICAL MONOCYTES
KETAMINE
NMDAR
mTOR PATHWAY
ANTI-INFLAMMATORY M2 MACROPHAGES
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
https://purl.org/becyt/ford/3.2
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Background: Depression is a highly prevalent disorder that is one of the leading causes of disability worldwide. Despite an unknown aetiology, evidence suggests that the innate and adaptive immune systems play a significant role in the development and maintenance of major depressive disorder (MDD). The non-competitive glutamatergic N-methyl-D-aspartate receptor (NMDAR) antagonist, (R,S)-ketamine (ketamine), has demonstrated rapid and robust efficacy as an antidepressant when administered at sub-anaesthetic doses. Methods: Our goal was to characterize the pro-inflammatory profile of patients with MDD by measuring proinflammatory cytokines in plasma and circulating monocyte subsets and to understand how ketamine induces an anti-inflammatory program in monocyte and macrophages in vitro and vivo. Finding: Our results show that patients with MDD without other comorbidities (N= 33) exhibited significantly higher levels of pro-inflammatory IL-12 and IL-6 in plasma and that these cytokines were associated with increased numbers of non-classical (CD11b+ CD16brightCD14neg) monocytes and increased activation state (CD40+ CD86+ ) of classical monocytes in circulation. Remarkably, we have demonstrated that sub-anaesthetic doses of ketamine programs human monocytes into M2c-like macrophages by inducing high levels of CD163 and MERTK with intermediate levels of CD64 and stimulating mTOR-associated gene expression in vitro. The NMDAR antagonist MK-801, but not the a-amino-3‑hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) antagonist, NBQX, also polarizes macrophages to an M2c-like phenotype, but this phenotype disappears upon mTOR pathway inhibition. Subanaesthetic doses (10 mg/kg) of ketamine administration in mice both promote reduction of circulating classical pro-inflammatory monocytes and increase of alternative M2 macrophage subtypes in the spleen and CNS. Interpretation: Our results suggest an anti-inflammatory property of ketamine that can skew macrophages to an M2-like phenotype, highlighting potential therapeutic implications not only for patients with MDD but also other inflammatory-based diseases.
Fil: Nowak, Wanda. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Farmacologia.; Argentina
Fil: Grendas, Leandro Nicolás. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Farmacologia.; Argentina
Fil: Sanmarco, Liliana María. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Estecho, Ivana Gisele. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Farmacologia.; Argentina
Fil: Arena, Ángeles Romina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Farmacologia.; Argentina
Fil: Eberhardt, Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Rodante, Demián Emanuel. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Farmacologia.; Argentina
Fil: Aoki, María Pilar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina
Fil: Daray, Federico Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Farmacologia.; Argentina
Fil: Carrera Silva, Eugenio Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Errasti, Andrea Emilse. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Farmacologia.; Argentina
description Background: Depression is a highly prevalent disorder that is one of the leading causes of disability worldwide. Despite an unknown aetiology, evidence suggests that the innate and adaptive immune systems play a significant role in the development and maintenance of major depressive disorder (MDD). The non-competitive glutamatergic N-methyl-D-aspartate receptor (NMDAR) antagonist, (R,S)-ketamine (ketamine), has demonstrated rapid and robust efficacy as an antidepressant when administered at sub-anaesthetic doses. Methods: Our goal was to characterize the pro-inflammatory profile of patients with MDD by measuring proinflammatory cytokines in plasma and circulating monocyte subsets and to understand how ketamine induces an anti-inflammatory program in monocyte and macrophages in vitro and vivo. Finding: Our results show that patients with MDD without other comorbidities (N= 33) exhibited significantly higher levels of pro-inflammatory IL-12 and IL-6 in plasma and that these cytokines were associated with increased numbers of non-classical (CD11b+ CD16brightCD14neg) monocytes and increased activation state (CD40+ CD86+ ) of classical monocytes in circulation. Remarkably, we have demonstrated that sub-anaesthetic doses of ketamine programs human monocytes into M2c-like macrophages by inducing high levels of CD163 and MERTK with intermediate levels of CD64 and stimulating mTOR-associated gene expression in vitro. The NMDAR antagonist MK-801, but not the a-amino-3‑hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) antagonist, NBQX, also polarizes macrophages to an M2c-like phenotype, but this phenotype disappears upon mTOR pathway inhibition. Subanaesthetic doses (10 mg/kg) of ketamine administration in mice both promote reduction of circulating classical pro-inflammatory monocytes and increase of alternative M2 macrophage subtypes in the spleen and CNS. Interpretation: Our results suggest an anti-inflammatory property of ketamine that can skew macrophages to an M2-like phenotype, highlighting potential therapeutic implications not only for patients with MDD but also other inflammatory-based diseases.
publishDate 2019
dc.date.none.fl_str_mv 2019-12
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/11336/106773
Nowak, Wanda; Grendas, Leandro Nicolás; Sanmarco, Liliana María; Estecho, Ivana Gisele; Arena, Ángeles Romina; et al.; Pro-inflammatory monocyte profile in patients with major depressive disorder and suicide behaviour and how ketamine induces antiinflammatory M2 macrophages by NMDAR and mTOR; The Lancet; EBioMedicine; 50; 12-2019; 290-305
2352-3964
CONICET Digital
CONICET
url http://hdl.handle.net/11336/106773
identifier_str_mv Nowak, Wanda; Grendas, Leandro Nicolás; Sanmarco, Liliana María; Estecho, Ivana Gisele; Arena, Ángeles Romina; et al.; Pro-inflammatory monocyte profile in patients with major depressive disorder and suicide behaviour and how ketamine induces antiinflammatory M2 macrophages by NMDAR and mTOR; The Lancet; EBioMedicine; 50; 12-2019; 290-305
2352-3964
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://linkinghub.elsevier.com/retrieve/pii/S2352396419307406
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.ebiom.2019.10.063
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv The Lancet
publisher.none.fl_str_mv The Lancet
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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score 13.22299

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