Review
T helper 17 cells may drive neuroprogression in major depressive disorder: Proposal of an integrative model

https://doi.org/10.1016/j.neubiorev.2016.02.002Get rights and content

Highlights

  • The pathophysiology of major depressive disorder remains elusive.

  • Immune activation and related processes are key in the pathophysiology of depression.

  • T helper 17 (Th17) cells may play a pivotal role in depression.

  • Th17 cells are important targets to be considered in future research.

Abstract

The exact pathophysiology of major depressive disorder (MDD) remains elusive. The monoamine theory, which hypothesizes that MDD emerges as a result of dysfunctional serotonergic, dopaminergic and noradrenergic pathways, has guided the therapy of this illness for several decades. More recently, the involvement of activated immune, oxidative and nitrosative stress pathways and of decreased levels of neurotrophic factors has provided emerging insights regarding the pathophysiology of MDD, leading to integrated theories emphasizing the complex interplay of these mechanisms that could lead to neuroprogression. In this review, we propose an integrative model suggesting that T helper 17 (Th17) cells play a pivotal role in the pathophysiology of MDD through (i) microglial activation, (ii) interactions with oxidative and nitrosative stress, (iii) increases of autoantibody production and the propensity for autoimmunity, (iv) disruption of the blood–brain barrier, and (v) dysregulation of the gut mucosa and microbiota. The clinical and research implications of this model are discussed.

Introduction

Major depressive disorder (MDD) is a chronic psychiatric condition with a lifetime prevalence of approximately 16% (Kessler et al., 2003) and heritability estimated to lie between 31 and 42% (Sullivan et al., 2000). MDD has been viewed primarily as a disorder centered around the dysfunction of monoaminergic pathways, namely those of serotonin, dopamine and noradrenaline (Elhwuegi, 2004). However, recent evidence shows that the neurotrophin, immune-inflammatory (Maes, 1995, Miller et al., 2009), and oxidative and nitrosative stress (O&NS) (Maes, 2008, Sarandol et al., 2007) pathways are also involved. It has been postulated that these systems interact in the pathophysiology of MDD to drive brain structural and functional alterations in a process referred to as neuroprogression (Moylan et al., 2013).

The trajectories of MDD frequently include recurrence and relapse (Mueller et al., 1999) and are often complicated by numerous psychiatric comorbidities (Kessler et al., 2003), such as neurodegenerative disorders that appear to share immune-inflammatory pathways (Anderson et al., 2013), and neurotransmitter alterations (Anisman et al., 2008). The increased length and number of episodes experienced may be related to a decreased efficacy of MDD treatment (Altamura et al., 2011, Black et al., 1989, Okuda et al., 2010) and an increased likelihood of relapse (Kendler et al., 2001). Additionally, an earlier onset of MDD is correlated with a worse prognosis, including longer episodes, increased risks of recurrence and comorbidities (Klein et al., 1999) and greater functional impairment (Zisook et al., 2007). This indicates an accumulation of effects and the progression of MDD symptomatology.

The exacerbation in depressive symptoms is also accompanied by structural and functional changes. Hippocampal volume reductions correlate with increased numbers of MDD episodes (Videbech and Ravnkilde, 2004) and with the duration of untreated MDD (Sheline et al., 2003). Changes in the activation and volume of the amygdala (Hastings et al., 2004) and the prefrontal (Botteron et al., 2002) and anterior cingulate cortices (Malykhin et al., 2012) have also been described. Notwithstanding the clinical, neuropsychological and neuroanatomical evidence that appears to support the neuroprogression hypothesis, the specific pathways involved in this process have recently been described in more detail. These include O&NS and mitochondrial dysfunction (Moylan et al., 2014) and aberrations in neurotransmitters (Fakhoury, 2015), neurotrophic factors (Tanis et al., 2007), cytokines, immune response mediators (Bakunina et al., 2015, Dantzer et al., 2008, Dowlati et al., 2010), glial cell interactions with the immune system (Pav et al., 2008) and gut–brain interactions (Dinan and Cryan, 2013).

T helper 17 (Th17) cells are a relatively novel class of T helper (Th) lymphocytes and represent a lineage that is independent of Th1 and Th2 cells (Harrington et al., 2005, Park et al., 2005). Th17 cells, which largely produce pro-inflammatory cytokines (Geboes et al., 2009, Ivanov et al., 2006) and attract macrophages and neutrophils to sites of infection or injury (Dong, 2008), have progressively been linked to inflammatory and autoimmune disorders (Bettelli et al., 2007). Evidence indicates that these cells may contribute to the emergence of autoimmunity (Burkett et al., 2015, Wienke et al., 2015), atopic diseases (Eyerich and Novak, 2013), and abnormalities in the gut-brain axis (Wang et al., 2014b). In addition, emerging data implicate Th17 cells in the pathophysiology of several neuro-immune diseases, e.g., schizophrenia (Debnath and Berk, 2014), multiple sclerosis (Abdolahi et al., 2015), and Alzheimer’s disease (Saresella et al., 2011).

Here, we improve the neuroprogression model of MDD, building upon a previous proposal that Th17 cells may play a role in the pathophysiology of MDD (Chen et al., 2011). We first review the main mechanisms associated with neuroprogression and autoimmunity in MDD. Then, we review the physiology of Th17 cells, provide evidence supporting a putative role for Th17 cells in the pathophysiology of MDD, and discuss how current and novel treatments may target these immune cells. Lastly, we propose an integrative model describing the various routes through which Th17 cells may contribute to MDD-related neuroprogression.

Section snippets

Serotonin (5-HT)

Abnormalities in neurotransmitter systems have been classically thought to play a pivotal role in the pathophysiology of MDD. The traditional hypothesis suggests that monoamine imbalance, especially of 5-HT, is central in the process (Hirschfeld, 2000). Nevertheless, a role for 5-HT acting as a neurotrophic factor has recently been suggested as a mechanism in the neuroprogression of this disorder (Djavadian, 2004). Autoimmune activity against 5-HT is a putative mechanism for 5-HT depletion, and

Autoantibodies in MDD

Autoantibodies in MDD may arise from neoepitopes produced by oxidation (Maes et al., 2013b). They can participate in MDD pathophysiology through several mechanisms, including the creation of immune complexes in the brain, the initiation of apoptosis, the reduction of neurotransmitter receptors and the regulation of monoamine levels (Iseme et al., 2014). Antibodies against the 5-HT1A serotonin receptor, muscarinic M1 acetylcholine receptor, μ-opioid receptor and D2 dopamine receptor have been

The differentiation and regulation of Th17 cells

Antigen-presenting cells induce the differentiation of antigen-specific naïve Th cells into effector T cells, which are further differentiated into lineages by cytokine activity (Dong, 2011). In the case of Th17 cells, the major cytokines active in this process are a combination of IL-21 and transforming growth factor-β (TGF-β) or IL-6 and TGF-β (Dong, 2008), which are cytokines produced by Th1 and Th2 lymphocytes, among other cell types. These cytokines exert their effects after the initial

Th17 actions in the CNS

Th17 can migrate to the CNS, although the processes behind the migration have been not been extensively investigated. CCL20 and chemokine receptor 6 are proposed to play a role in central access via the choroid plexus (Zhang et al., 2013). The epithelium of the choroid plexus expresses CCL20, which may thus allow the entry of Th17 cells into the subarachnoid space, thereby triggering inflammation (Reboldi et al., 2009, Sie et al., 2014).

The role of intracranial IL-17 has been addressed in

Studies of the putative role of Th17 cells in MDD

We summarized all the studies evaluating the role of Th17 cells in MDD in Table 1. Table 1A presents the findings of studies in humans, while Table 1B presents studies conducted using mouse models of MDD.

Conclusions and future directions

Taken together, the studies investigating Th17 and IL-17 in MDD provide evidence of a role for Th17 cell changes in this condition. The proportion of Th17 cells changes in relation to the proportions of other Th cells in mouse models of MDD (Beurel et al., 2013, Hong et al., 2012), and the levels of Th17 cells, as well as of IL-17A, are subdued by actions of mood-regulating medications, including SSRIs, lithium, and tricyclic antidepressants (Kim et al., 2013, Zhang et al., 2012). Such Th17 and

Acknowledgements

AFC and JQ are recipients of research fellowship awards from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; Brazil). CAK is the recipient of a postdoctoral fellowship award from CAPES (Brazil). GSA is supported by an international postdoctoral fellowship from CNPq (Brazil). MB is supported by an NHMRC Senior Principal Research Fellowship 1059660. The Laboratory of Neurosciences (Brazil) is one of the centers of the National Institute for Molecular Medicine (INCT-MM)

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