TY  - JOUR
PY  - 2019//
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
JO  - EBioMedicine
A1  - Nowak, Wanda
A1  - Grendas, Leandro Nicolás
A1  - Sanmarco, Liliana María
A1  - Estecho, Ivana Gisele
A1  - Arena, Ángeles Romina
A1  - Eberhardt, Natalia
A1  - Rodante, Demián Emanuel
A1  - Aoki, María Pilar
A1  - Daray, Federico Manuel
A1  - Carrera Silva, Eugenio Antonio
A1  - Errasti, Andrea Emilse
SP  - ePub
EP  - ePub
VL  - ePub
IS  - ePub
N2  - 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. <br><br>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<sup>+</sup>CD16<sup>bright</sup>CD14<sup>neg</sup>) monocytes and increased activation state (CD40<sup>+</sup>CD86<sup>+</sup>) 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-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. <br><br>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).<br><br>Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.<p />  <p>Language: en</p>
LA  - en
SN  - 2352-3964
UR  - http://dx.doi.org/10.1016/j.ebiom.2019.10.063
ID  - ref1
ER  -