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

EBioMedicine. 2019 Dec;50:290-305. doi: 10.1016/j.ebiom.2019.10.063. Epub 2019 Nov 18.

Abstract

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-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 Científicas y Técnicas (CONICET) and Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT-FONCYT).

Keywords: Anti-inflammatory M2 macrophages; Depression; IL-12; Ketamine; NMDAR; Non-classical monocytes; mTOR pathway.

MeSH terms

  • Adult
  • Animals
  • Biomarkers
  • Cytokines / blood
  • Cytokines / metabolism*
  • Depressive Disorder, Major / etiology*
  • Depressive Disorder, Major / metabolism*
  • Depressive Disorder, Major / psychology
  • Disease Models, Animal
  • Female
  • Gene Expression Regulation / drug effects
  • Humans
  • Immunophenotyping
  • Inflammation Mediators / blood
  • Inflammation Mediators / metabolism*
  • Ketamine / metabolism
  • Ketamine / pharmacology
  • Macrophages / drug effects
  • Macrophages / metabolism*
  • Male
  • Mice
  • Middle Aged
  • Monocytes / drug effects
  • Monocytes / metabolism*
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Signal Transduction / drug effects
  • Suicide
  • TOR Serine-Threonine Kinases / metabolism*
  • Young Adult

Substances

  • Biomarkers
  • Cytokines
  • Inflammation Mediators
  • Receptors, N-Methyl-D-Aspartate
  • Ketamine
  • MTOR protein, human
  • TOR Serine-Threonine Kinases