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, W; GRENDAS, LN; SANMARCO, LM; ESTECHO, IG; ARENA, AR; EBERHARDT, N; RODANTE, DE; AOKI, MP; DARAY, FM; CARRERA-SILVA, EA; ERRASTI, AE

EBioMedicine

Elsevier

Año: 2019

Depression is adevastating disorder that is one of the leading causes of disability worldwide.Despite an unknown etiology, evidence suggests that the innate and adaptiveimmune systems play a significant role in the development and maintenance of majordepressive disorder (MDD). The noncompetitive glutamatergicN-methyl-D-aspartate receptor (NMDAR) antagonist, (R,S)-ketamine (ketamine),has demonstrated rapid and robust efficacy as an antidepressant whenadministered at sub-anesthetic doses. Our goal was to characterize thepro-inflammatory profile of patients with MDD and to understand how ketamineinduces an anti-inflammatory program in macrophages. Our results show that patientswith MDD without other comorbidities (N=33) exhibited significant higher levelsof pro-inflammatory IL-12 and IL-6, and these cytokines were associated with increasednumbers of non-classical (CD11b++CD16brightCD14neg)monocyte and increased activation state (CD40+CD86+) ofclassical monocytes. Remarkably, we have demonstrated that ketamine programshuman monocytes into M2c-like macrophages by inducing high levels of CD163 andMERTK with intermediate levels of CD64 and stimulating mTOR-associated geneexpression. The NMDAR antagonist MK-801, but not the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionicacid receptor (AMPAR) antagonist, NBQX, also polarizes macrophages to an M2c-likephenotype, but this phenotype disappears upon mTOR pathway inhibition. Sub-anestheticdoses (10 mg/kg) of ketamine administration both promotes reduction ofcirculating classical pro-inflammatory monocytes and increase of alternative M2macrophage subtypes in the spleen and CNS of the mouse. In conclusion, ourresults suggest an anti-inflammatory property of ketamine that can skew macrophagesto an M2-like phenotype, highlighting potential therapeutic implications notonly for patients with MDD but also other inflammatory-based diseases