Review
Mechanistic explanations how cell-mediated immune activation, inflammation and oxidative and nitrosative stress pathways and their sequels and concomitants play a role in the pathophysiology of unipolar depression

https://doi.org/10.1016/j.neubiorev.2011.12.005Get rights and content

Abstract

This paper reviews that cell-mediated-immune (CMI) activation and inflammation contribute to depressive symptoms, including anhedonia; anxiety-like behaviors; fatigue and somatic symptoms, e.g. illness behavior or malaise; and mild cognitive impairment (MCI). These effects are in part mediated by increased levels of pro-inflammatory cytokines (PICs), e.g. interleukin-1 (IL-1), IL-6 and tumor necrosis factor (TNF)α, and Th-1-derived cytokines, such as IL-2 and interferon (IFN)γ. Moreover, new pathways, i.e. concomitants and sequels of CMI activation and inflammation, were detected in depression: (1) Induction of indoleamine 2,3-dioxygenase (IDO) by IFNγ and some PICs is associated with depleted plasma tryptophan, which may interfere with brain 5-HT synthesis, and increased production of anxiogenic and depressogenic tryptophan catabolites. (2) Increased bacterial translocation may cause depression-like behaviors by activating the cytokine network, oxidative and nitrosative stress (O&NS) pathways and IDO. (3) Induction of O&NS causes damage to membrane ω3 PUFAs, functional proteins, DNA and mitochondria, and autoimmune responses directed against intracellular molecules that may cause dysfunctions in intracellular signaling. (4) Decreased levels of ω3 PUFAs and antioxidants, such as coenzyme Q10, glutathione peroxidase or zinc, are associated with an increased inflammatory potential; more oxidative damage; the onset of specific symptoms; and changes in the expression or functions of brain 5-HT and N-methyl-d-aspartate receptors. (5) All abovementioned factors cause neuroprogression, that is a combination of neurodegeneration, neuronal apoptosis, and lowered neurogenesis and neuroplasticity. It is concluded that depression may be the consequence of a complex interplay between CMI activation and inflammation and their sequels/concomitants which all together cause neuroprogression that further shapes the depression phenotype. Future research should employ high throughput technologies to collect genetic and gene expression and protein data from patients with depression and analyze these data by means of systems biology methods to define the dynamic interactions between the different cell signaling networks and O&NS pathways that cause depression.

Highlights

► Depression is accompanied by immune activation, inflammation and neuroprogression. ► Immune activation and inflammation may cause neuroprogression and depression. ► Sequels and concomitants of immune activation and inflammation play a key role in depression. ► Key players are: tryptophan and 5-HT, oxidative stress, antioxidants, omega-3, and leaky gut. ► Depression is the consequence of a complex interplay between these different pathways.

Introduction

There is evidence that unipolar depression is associated with a chronic, low grade inflammation and cell-mediated immune (CMI) activation (Maes et al., 1990, Maes et al., 1991, Maes et al., 1992). Since these first results (1990–1992), many papers have been published on inflammatory and CMI biomarkers in depression as evidenced by the publication of two meta-analyses which underscored that depression is associated with signs of inflammation (Dowlati et al., 2010) and T cell activation (Liu et al., 2011). Moreover, new pathways, i.e. concomitants and sequels of CMI activation and inflammation, were discovered in depression, e.g. activation of indoleamine 2,3-dioxygenase (IDO) (Maes et al., 1993a, Maes et al., 1994); increased translocation of gram-negative bacteria (Maes et al., 2008); decreased antioxidant levels and increased oxidative and nitrosative stress (O&NS) pathways (Maes et al., 2000b, Maes et al., 2011a, Bilici et al., 2001); lowered levels of zinc (Maes et al., 1997b) and ω3 polyunsaturated fatty acids (PUFAs) (Maes et al., 1999a); and damage to mitochondria (Gardner and Boles, 2011).

Parallel to the progress made in the field of inflammation and CMI activation, new findings showed progressive neuroanatomical dysfunctions in depression, such as neurodegeneration, increased neuronal apoptosis, reduced neurogenesis and lowered neurotrophic factors as well as a neurocognitive decline in depression (Duman and Monteggia, 2006, Maes et al., 2009c, Catena-Dell’Osso et al., 2011). Neuroprogression is a new label that was introduced to denote the abovementioned progressive neuroanatomical and neuronal dysfunctions (Berk et al., 2011).

The main aims of this paper are to explain how the various inflammatory and CMI pathways as well as their sequels and concomitants contribute to the pathophysiology of unipolar depression and may be associated with the onset of depression; and how all those factors act in concert to cause the neuroprogressive aberrations described in depression. Towards this end we will briefly review the CMI and inflammatory findings in clinical depression and the body of evidence that CMI activation, including increased production of interferon-γ (IFNγ) and interleukin-2 (IL-2); and pro-inflammatory cytokines (PICs), such as IL-1β, IL-6 and tumor necrosis factor-α (TNFα), may cause depressive-like behaviors, including melancholic symptoms (anhedonia); anxiety; fatigue and somatic symptoms; and neurocognitive symptoms as well. The symptomatology of human depression is indeed very complex and consists of different, albeit overlapping symptom dimensions: (a) the melancholic dimension, characterized by a distinct quality of depressed mood (anhedonia), non-reactivity, early morning awakening, anorexia, body weight loss, and cognitive and psychomotor disturbances; (b) the anxiety dimension, with tension, anxious behavior, and respiratory, genito-urinary and autonomic symptoms; (c) the fatigue and somatic dimension, with aches and pain, muscular tension, fatigue, concentration difficulties, failing memory, irritability, irritable bowel, headache, and a flu-like malaise; and (d) neurocognitive disorders, including mild cognitive impairment (MCI) (Maes, 2009).

To comprehend the mechanisms that may explain the effects of CMI activation and inflammation we will focus on the new pathways, i.e. the sequels and concomitants of CMI activation and inflammation, that underpin the pathophysiology of depression and that in concert with the aforementioned cytokines contribute to the pathology of depression. We will describe how all these events together contribute to the neuroprogressive processes in depression. For a description of the various pathways involved in bipolar depression we refer the readers to a recent review in the same journal (Berk et al., 2011).

Section snippets

Cell-mediated immune activation and inflammation

CMI is that component of the immune system that involves interactions between different immune cells, including T lymphocytes and macophages/monocytes and that does not involve complement, the acute phase response or antibodies. Once triggered, T cells are activated, acquire receptors, e.g. the IL-2 receptor (IL-2R or CD25) and produce T cell derived cytokines, such as IFNγ and IL-2, which will activate monocytes/macrophages (Wachter et al., 1992). The latter in turn will produce cytokines,

Cytokine-induced changes in 5-HT receptors

Aberrations in the metabolism of 5-HT are involved in the pathophysiology of depression, e.g. changes in 5-HT mediated second-messenger signaling and changes in SERT, 5-HT2 and 5-HT1A receptors and a lowered availability of plasma tryptophan (the precursor of 5-HT) to the brain (Maes and Meltzer, 1995, Plein and Berk, 2000, Plein et al., 2000). SERT regulates the synaptic availability of 5-HT in the CNS and is therefore employed as the major target of currently available antidepressant drugs. A

Increased immune responses against LPS in depression

In the gut, epithelial cells surround the gut wall and form a tight junction barrier that segregates the luminal bacteria, including gram-negative commensal bacteria, from the interstitium. Inflammatory processes may cause a loosening of the tight junction barrier through the effects of NFκB (Al-Sadi and Ma, 2007, Ma et al., 2005); IL-1β, IL-6, TNFα, and IFNγ (Clark et al., 2005, Chavez et al., 1999); increased O&NS and a reduction in antioxidants (Wu et al., 2004b). The subsequent loosening of

Activated O&NS pathways in depression

Inflammatory and CMI responses are accompanied by increased production of radical oxygen (ROS) and radical nitrogen species (RNS). PICs, such as IL-1 and TNFα, enhance the effects of ROS including hydrogen peroxide, while neopterin enhances iNOS gene expression causing increased nitric-oxide production (Maes et al., in press). O&NS processes react with proteins, fatty acids, DNA, including mitochondrial DNA (mtDNA), causing damage to these molecules and the tissues to which they belong. O&NS

Decreased antioxidant levels in depression

Antioxidants, antioxidant enzymes and some proteins tightly regulate ROS and RNS by scavenging or binding ROS/RNS or decreasing ROS/RNS production. Coenzyme Q10, vitamins C and E, and glutathione are important antioxidants. Superoxide dismutase (SOD) and glutathione peroxidase (GPX) are examples of antioxidant enzymes that neutralize peroxides and superoxide. APPs, such as haptoglobin and albumin, function as antioxidants by binding ROS and RNS. Tryptophan and tyrosine residues have important

Lowered zinc in depression

Zinc is a trace element that is needed for the confirmation of polysomes during protein synthesis, and the stabilization of membranes. Zinc functions as an important cofactor for several pathways and enzymes, like metalloenzymes and zinc-dependent enzymes. Zinc has a key role in signal transduction and gene expression, including that of cytokine genes, and plays a key role in synaptic plasticity and glutaminergic neurons (Maes et al., 1997b, Szewczyk et al., 2011). During inflammatory

Dysfunctional mitochondria in depression

Mitochondria produce most of the energy for the cell, stored as ATP, through β-oxidative processes. The latter constantly generate ROS/RNS that may damage mtDNA and lipid membrane structures of mitochondria. Specific antioxidants, such as coenzyme Q10, lipoic acid and GPX protect the mitochondria, including mtDNA, against these damaging effects (Chaturvedi and Beal, 2008, Liu, 2008).

Depression is accompanied by mitochondrial disturbances, such as deletions of mtDNA (Shao et al., 2008, Gardner

Lower omega-3 PUFAs in depression

There is now evidence for lowered ω3 PUFA contents, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the serum, red blood cell (RBC) membrane, fat tissues and the brain of depressed patients, while no changes in ω6 PUFA contents are found (Maes et al., 1999a, Peet et al., 1998, Mamalakis et al., 2006, Lin et al., 2010). Epidemiologic studies show that a low dietery intake of EPA and DHA is associated with higher prevalence rates of depression and postpartum depression (

Neuroprogression in depression

There is now evidence that neuroprogression plays a role in the pathophysiology of depression (Sapolsky, 2004, Henn and Vollmayr, 2004, Maes et al., 2009c, Maes et al., 2011d, Berk et al., 2011). Volumetric changes in hippocampus, amygdala, prefrontal cortex, anterior cingulate and basal ganglia have been detected in patients suffering from long-term recurrent depression (Campbell and MacQueen, 2006). Hippocampal volume reduction is associated with the neurocognitive deficits found in mood

Conclusions and directions for future research

Fig. 3 depicts an overview of the main interconnections in the IO&NS pathways and their sequels that are involved in the pathophysiology of depression. Many of these pathways are actually still under investigation and are strongly debated. Our review shows that many different peripheral and central pathways related to CMI activation, inflammation and O&NS are related to the onset of depressive symptoms and through modulation of other functions, such as the TRYCAT pathway and ω3 PUFAs or serum

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