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Pro-inflammatory monocyte profile in patients with major depressive disorder and suicide behaviour and how ketamine induces anti-inflammatory M2 macrophages by NMDAR and mTOR.
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.
Afiliação
  • Nowak W; Instituto de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, 9th floor, Buenos Aires 1121, Argentina.
  • Grendas LN; Instituto de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, 9th floor, Buenos Aires 1121, Argentina.
  • Sanmarco LM; Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
  • Estecho IG; Instituto de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, 9th floor, Buenos Aires 1121, Argentina.
  • Arena ÁR; Instituto de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, 9th floor, Buenos Aires 1121, Argentina.
  • Eberhardt N; Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
  • Rodante DE; Instituto de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, 9th floor, Buenos Aires 1121, Argentina.
  • Aoki MP; Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
  • Daray FM; Instituto de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, 9th floor, Buenos Aires 1121, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina. Electronic address: fdaray@hotmail.com.
  • Carrera Silva EA; Instituto de Medicina Experimental (IMEX), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Academia Nacional de Medicina, Pacheco de Melo 3081, Buenos Aires 1425, Argentina. Electronic address: carrerasilva@yahoo.com.ar.
  • Errasti AE; Instituto de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, 9th floor, Buenos Aires 1121, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina. Electronic address: andreaerrasti@gmail.com.
EBioMedicine ; 50: 290-305, 2019 Dec.
Article em En | MEDLINE | ID: mdl-31753725
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 pro-inflammatory 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 α-amino-3­hydroxy-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. Sub-anaesthetic 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. FUNDING: This study was supported by grants from the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) and Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT-FONCYT).
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Monócitos / Citocinas / Receptores de N-Metil-D-Aspartato / Mediadores da Inflamação / Transtorno Depressivo Maior / Serina-Treonina Quinases TOR / Macrófagos Tipo de estudo: Prognostic_studies Limite: Adult / Animals / Female / Humans / Male / Middle aged Idioma: En Revista: EBioMedicine Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Argentina País de publicação: Holanda

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Monócitos / Citocinas / Receptores de N-Metil-D-Aspartato / Mediadores da Inflamação / Transtorno Depressivo Maior / Serina-Treonina Quinases TOR / Macrófagos Tipo de estudo: Prognostic_studies Limite: Adult / Animals / Female / Humans / Male / Middle aged Idioma: En Revista: EBioMedicine Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Argentina País de publicação: Holanda