PMID- 31753725
OWN - NLM
STAT- MEDLINE
DCOM- 20200430
LR  - 20211204
IS  - 2352-3964 (Electronic)
IS  - 2352-3964 (Linking)
VI  - 50
DP  - 2019 Dec
TI  - 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.
PG  - 290-305
LID - S2352-3964(19)30740-6 [pii]
LID - 10.1016/j.ebiom.2019.10.063 [doi]
AB  - 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(+)CD16(bright)CD14(neg)) 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 
      alpha-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. 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 Cientificas y Tecnicas 
      (CONICET) and Agencia Nacional de Promocion Cientifica y Tecnologica 
      (ANPCyT-FONCYT).
CI  - Copyright (c) 2019 The Authors. Published by Elsevier B.V. All rights reserved.
FAU - Nowak, Wanda
AU  - Nowak W
AD  - Instituto de Farmacologia, Facultad de Medicina, Universidad de Buenos Aires, 
      Paraguay 2155, 9th floor, Buenos Aires 1121, Argentina.
FAU - Grendas, Leandro Nicolas
AU  - Grendas LN
AD  - Instituto de Farmacologia, Facultad de Medicina, Universidad de Buenos Aires, 
      Paraguay 2155, 9th floor, Buenos Aires 1121, Argentina.
FAU - Sanmarco, Liliana Maria
AU  - Sanmarco LM
AD  - Centro de Investigaciones en Bioquimica Clinica e Inmunologia (CIBICI), Consejo 
      Nacional de Investigaciones Cientificas y Tecnologicas (CONICET), Departamento de 
      Bioquimica Clinica, Facultad de Ciencias Quimicas, Universidad Nacional de 
      Cordoba, Cordoba, Argentina.
FAU - Estecho, Ivana Gisele
AU  - Estecho IG
AD  - Instituto de Farmacologia, Facultad de Medicina, Universidad de Buenos Aires, 
      Paraguay 2155, 9th floor, Buenos Aires 1121, Argentina.
FAU - Arena, Angeles Romina
AU  - Arena AR
AD  - Instituto de Farmacologia, Facultad de Medicina, Universidad de Buenos Aires, 
      Paraguay 2155, 9th floor, Buenos Aires 1121, Argentina.
FAU - Eberhardt, Natalia
AU  - Eberhardt N
AD  - Centro de Investigaciones en Bioquimica Clinica e Inmunologia (CIBICI), Consejo 
      Nacional de Investigaciones Cientificas y Tecnologicas (CONICET), Departamento de 
      Bioquimica Clinica, Facultad de Ciencias Quimicas, Universidad Nacional de 
      Cordoba, Cordoba, Argentina.
FAU - Rodante, Demian Emanuel
AU  - Rodante DE
AD  - Instituto de Farmacologia, Facultad de Medicina, Universidad de Buenos Aires, 
      Paraguay 2155, 9th floor, Buenos Aires 1121, Argentina.
FAU - Aoki, Maria Pilar
AU  - Aoki MP
AD  - Centro de Investigaciones en Bioquimica Clinica e Inmunologia (CIBICI), Consejo 
      Nacional de Investigaciones Cientificas y Tecnologicas (CONICET), Departamento de 
      Bioquimica Clinica, Facultad de Ciencias Quimicas, Universidad Nacional de 
      Cordoba, Cordoba, Argentina.
FAU - Daray, Federico Manuel
AU  - Daray FM
AD  - Instituto de Farmacologia, Facultad de Medicina, Universidad de Buenos Aires, 
      Paraguay 2155, 9th floor, Buenos Aires 1121, Argentina; Consejo Nacional de 
      Investigaciones Cientificas y Tecnicas (CONICET), Buenos Aires, Argentina. 
      Electronic address: fdaray@hotmail.com.
FAU - Carrera Silva, Eugenio Antonio
AU  - Carrera Silva EA
AD  - Instituto de Medicina Experimental (IMEX), Consejo Nacional de Investigaciones 
      Cientificas y Tecnicas (CONICET), Academia Nacional de Medicina, Pacheco de Melo 
      3081, Buenos Aires 1425, Argentina. Electronic address: 
      carrerasilva@yahoo.com.ar.
FAU - Errasti, Andrea Emilse
AU  - Errasti AE
AD  - Instituto de Farmacologia, Facultad de Medicina, Universidad de Buenos Aires, 
      Paraguay 2155, 9th floor, Buenos Aires 1121, Argentina; Consejo Nacional de 
      Investigaciones Cientificas y Tecnicas (CONICET), Buenos Aires, Argentina. 
      Electronic address: andreaerrasti@gmail.com.
LA  - eng
PT  - Journal Article
DEP - 20191118
PL  - Netherlands
TA  - EBioMedicine
JT  - EBioMedicine
JID - 101647039
RN  - 0 (Biomarkers)
RN  - 0 (Cytokines)
RN  - 0 (Inflammation Mediators)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 690G0D6V8H (Ketamine)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Adult
MH  - Animals
MH  - Biomarkers
MH  - Cytokines/blood/*metabolism
MH  - Depressive Disorder, Major/*etiology/*metabolism/psychology
MH  - Disease Models, Animal
MH  - Female
MH  - Gene Expression Regulation/drug effects
MH  - Humans
MH  - Immunophenotyping
MH  - Inflammation Mediators/blood/*metabolism
MH  - Ketamine/metabolism/pharmacology
MH  - Macrophages/drug effects/*metabolism
MH  - Male
MH  - Mice
MH  - Middle Aged
MH  - Monocytes/drug effects/*metabolism
MH  - Receptors, N-Methyl-D-Aspartate/*metabolism
MH  - Signal Transduction/drug effects
MH  - Suicide
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Young Adult
PMC - PMC6921226
OTO - NOTNLM
OT  - Anti-inflammatory M2 macrophages
OT  - Depression
OT  - IL-12
OT  - Ketamine
OT  - NMDAR
OT  - Non-classical monocytes
OT  - mTOR pathway
COIS- The authors have declared no potential conflicts of interest
EDAT- 2019/11/23 06:00
MHDA- 2020/05/01 06:00
PMCR- 2019/11/18
CRDT- 2019/11/23 06:00
PHST- 2019/05/12 00:00 [received]
PHST- 2019/09/17 00:00 [revised]
PHST- 2019/10/31 00:00 [accepted]
PHST- 2019/11/23 06:00 [pubmed]
PHST- 2020/05/01 06:00 [medline]
PHST- 2019/11/23 06:00 [entrez]
PHST- 2019/11/18 00:00 [pmc-release]
AID - S2352-3964(19)30740-6 [pii]
AID - 10.1016/j.ebiom.2019.10.063 [doi]
PST - ppublish
SO  - EBioMedicine. 2019 Dec;50:290-305. doi: 10.1016/j.ebiom.2019.10.063. Epub 2019 
      Nov 18.