Pro-inflammatory monocyte profile in patients with major depressive disorder and suicide behaviour and how ketamine induces antiinflammatory M2 macrophages by NMDAR and mTOR
| Autor: | Liliana Maria Sanmarco, Wanda Nowak, Eugenio Antonio Carrera Silva, Ángeles Romina Arena, Maria Pilar Aoki, Ivana Gisele Estecho, Andrea Emilse Errasti, Leandro Nicolás Grendas, Natalia Eberhardt, Demián Rodante, Federico Manuel Daray |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Research paper mTOR PATHWAY Poison control lcsh:Medicine Medicina Clínica Non-classical monocytes Monocytes Mice 0302 clinical medicine ANTI-INFLAMMATORY M2 MACROPHAGES purl.org/becyt/ford/3.2 [https] lcsh:R5-920 biology Depression TOR Serine-Threonine Kinases General Medicine purl.org/becyt/ford/3.1 [https] Middle Aged DEPRESSION Anti-inflammatory M2 macrophages NMDAR Suicide Medicina Básica mTOR pathway medicine.anatomical_structure Integrin alpha M IL-12 030220 oncology & carcinogenesis Cytokines Ketamine Female purl.org/becyt/ford/3 [https] Inflammation Mediators lcsh:Medicine (General) Signal Transduction Adult CIENCIAS MÉDICAS Y DE LA SALUD Inmunología Receptors N-Methyl-D-Aspartate General Biochemistry Genetics and Molecular Biology Immunophenotyping Young Adult 03 medical and health sciences Immune system medicine Animals Humans Psiquiatría NON-CLASSICAL MONOCYTES Depressive Disorder Major CD40 business.industry Macrophages Monocyte KETAMINE lcsh:R Antagonist MERTK Disease Models Animal 030104 developmental biology Gene Expression Regulation Immunology biology.protein business CD163 Biomarkers |
| Zdroj: | EBioMedicine, Vol 50, Iss, Pp 290-305 (2019) CONICET Digital (CONICET) Consejo Nacional de Investigaciones Científicas y Técnicas instacron:CONICET EBioMedicine |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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