Abstract
Several lines of evidence link macrophage activation and inflammation with (monoaminergic) nervous systems in the etiology of depression. IFN treatment is associated with depressive symptoms, whereas anti‐TNFα therapies elicit positive mood. This study describes the actions of 2 monoaminergic antidepressants (escitalopram, nortriptyline) and 3 anti‐inflammatory drugs (indomethacin, prednisolone, and anti‐TNFα antibody) on the response of human monocyte‐derived macrophages (MDMs) from 6 individuals to LPS or IFN‐α. Expression profiling revealed robust changes in the MDM transcriptome (3294 genes at P < 0.001) following LPS challenge, whereas a more limited subset of genes (499) responded to IFNα. Contrary to published reports, administered at nontoxic doses, neither monoaminergic antidepressant significantly modulated the transcriptional response to either inflammatory challenge. Each anti‐inflammatory drug had a distinct impact on the expression of inflammatory cytokines and on the profile of inducible gene expression—notably on the regulation of enzymes involved in metabolism of tryptophan. Inter alia, the effect of anti‐TNFα antibody confirmed a predicted autocrine stimulatory loop in human macrophages. The transcriptional changes were predictive of tryptophan availability and kynurenine synthesis, as analyzed by targeted metabolomic studies on cellular supernatants. We suggest that inflammatory processes in the brain or periphery could impact on depression by altering the availability of tryptophan for serotonin synthesis and/or by increasing production of neurotoxic kynurenine.
Highlights
We studied the action of two monoaminergic antidepressant drugs on monocytederived macrophages (MDMs), a selective serotonin reuptake inhibitors (SSRI) and a tricyclic antidepressant (TCA; nortriptyline)
In keeping with evidence that LPS-inducible genes in monocytes can be treated as quantitative traits with extensive variation between individuals,[51] samples from the same donor tended to be in the same neighborhood
We investigated the effects of LPS or IFNα challenge on gene expression by CSF1-cultured MDMs
Summary
Autoimmune and inflammatory diseases are commonly associated with mood disorders and several lines of evidence indicate inflammation may give rise to or exacerbate them.[1,2] Studies of animals exposed to proinflammatory challenges, ranging from LPS administration to social defeat, reveal that activation of the peripheral innate immune system causes a depression-like syndrome of illness behavior: social withdrawal, reduced mobility/energy, sleep disturbance, weight loss, and anhedonia.[3,4,5] In humans, IFNα-based therapy for hepatitis C infection can trigger a major depressive disorder (MDD) resulting in around 30% of patients withdrawing from treatment.[6,7] Abbreviations: COX, cyclooxygenase; MDD, major depressive disorder; MDMs, monocyte-derived macrophages; SSRI, selective serotonin reuptake inhibitors; TCA, tricyclic antidepressant. Received: 27 June 2017 Revised: 4 November 2017 J Leukoc Biol. 2018;103:681–692
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
