A Chicken and Egg Scenario in Psychoneuroimmunology - Bidirectional Mechanisms Linking Cytokines and Depression

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J Affect Disord Rep. Author manuscript; available in PMC 2022 December 01.
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Published in final edited form as:

J Affect Disord Rep. 2021 December ; 6: . doi:10.1016/j.jadr.2021.100177.
A chicken and egg scenario in psychoneuroimmunology:

Bidirectional mechanisms linking cytokines and depression
Manivel Rengasamya,*, Anna Marslandb, Meredith Spadaa, Kimberly Hsiungc, Tessa
Kovatsa, Rebecca B. Pricea,b
aDepartment of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA
bDepartment of Psychology, University of Pittsburgh, Pittsburgh, PA, USA
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cUniversity of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
Abstract
Background: Cytokines are an important part of the immune system. Certain cytokines, such
as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα), have well-described associations
with depression. Various mechanisms exist that may explain bidirectional effects of cytokines
on depression and vice versa. No recent reviews to our knowledge have comprehensively
characterized both these mechanisms and the interaction of these mechanisms using evidence
from the molecular level to the clinical level. The goal of this review is to both evaluate the present
knowledge base and identify knowledge gaps to help guide future research.
Methods: We conducted an extensive bibliographic search across multiple databases, using both
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general (e.g. “cytokine”) and topic-specific (e.g. “kynurenine”) keywords.
Results: We describe the most recent evidence outlining these mechanisms, including the role of
the hypothalamic pituitary axis, the kynurenine pathway, and neural circuitry. For relevant topics,
we outline the pathways by which cytokine activation may lead to depressive symptoms, and
how depressive symptomology may lead to elevations in cytokines. We also identify key areas
for future research, including the need for longitudinal clinical studies to examine causality in
pertinent mechanisms and modulating factors in the cytokine-depression interaction.
Limitations: Given the numerous potential mechanisms associating cytokines and depressions,
this review paper solely focuses on the most commonly described mechanisms at a basic level.
Conclusions: Bidirectional evidence exists for several mechanisms in the relationship between
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cytokines and depression. However, more work is required to further elucidate the role of these
mechanisms in specific clinical populations.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

*
Corresponding author at: Western Psychiatric Institute and Clinic, 3811 O’Hara St., Pittsburgh, PA 15213, USA.
rengasamym@upmc.edu (M. Rengasamy).
Declaration of Competing Interest
There are no conflicts of interest associated with any author.
Supplementary materials
Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.jadr.2021.100177.
Rengasamy et al. Page 2
Keywords
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Cytokines; Depression; Major depressive disorder; Inflammation; Interleukin-6;

Psychoneuroimmunology
1. Introduction
Major Depressive Disorder (MDD) ranks among one of the most disabling illnesses
worldwide, with significant personal and societal costs (Richards, 2011). More than 50%
of suicides occur in individuals with MDD, and thus MDD is specifically associated with
significant mortality (Henriksson et al., 1993). Although effective psychotropic medication
and psychotherapy treatments exist for individuals with MDD, not all depressed patients
are able to achieve remission of their symptoms even with treatment, leading to continued
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risk of depression-associated morbidity and mortality (Fekadu et al., 2009). The lack of
objective biomarkers and symptom heterogeneity make treatment of MDD difficult. Thus,
understanding of the varied neurobiological mechanisms of depression may be important in
developing efficacious and targeted treatments for depression.
The “inflammatory” hypothesis of depression has received increasing attention in recent

years and postulates that immune system activation and altered cytokine regulation are
associated with depressive disorders. Cytokines are small proteins released by immune
system cells in reaction to certain stimuli (e.g. bacteria or proteins associated with cell
death). From peripheral circulation, these cytokines can cross the blood brain barrier or
have effects on the blood brain barrier to affect brain neuron function, as described in prior
reviews (Supplemental Table 1) (Dantzer, 2001). The inflammatory hypothesis suggests that,
at least in a subset of depressed patients, inflammatory mechanisms related to cytokine
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activation (either in the periphery or the central nervous system (CNS)) are associated with
depression (Dantzer et al., 2008). Furthermore, the relationship between cytokine activation
and depression is likely bidirectional, with depression contributing to cytokine elevation
and vice versa (Amodeo et al., 2017; Young et al., 2014). Of note, the characterization of
depression as being a distinct concept from cytokine activation is part of a widely-used
conceptual framework within the fields of psychiatry and neuroscience, with the aim of
better understanding the pathophysiology of depression as well as the relationship between
the patient’s experience of depression symptoms and future inflammation. This perspective
is supported by studies that suggest a temporal distinction between the two processes, such
as those identifying that depressive symptoms at one point in time predict future cytokine
activation. However, an important alternative perspective is that cytokine activation and
depression may be part of a unitary syndrome that bridges both biological and psychological
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aspects simultaneously (Glannon, 2020; Miresco and Kirmayer, 2006).
The mechanisms for the bidirectional cytokine-depression relationship have previously been
partially reviewed by other authors, although often with limited specificity or attention to
the theoretical, molecular, preclinical, or clinical evidence for such mechanisms (Felger
and Lotrich, 2013; Jeon and Kim, 2016). Major mechanisms involved in this relationship
include neurotransmitters, neurocircuitry, the hypothalamic pituitary adrenal axis (HPA),
the sympathetic nervous system (SNS), and the kynurenine pathway, among others. In this
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review examining the latest evidence related to depression and cytokines (in both the blood
and brain), we hope to expound upon mechanisms of effects of cytokines on depression and
of depression on cytokines, ultimately to identify needed areas of future research.
2. Methods
We completed a structured narrative review by searching Google Scholar and PubMed using
a combination of keywords, including general keywords “depression,” “cytokines”, “major
depressive disorder,” “mechanism,” and “MDD”, and also topic-specific keywords (e.g.
“kynurenine” for the kynurenine pathway) when relevant. We examined at minimum the
top fifty most relevant peer-reviewed manuscripts (based on the search engine algorithm)
for each search or keyword. Topic and topic specific keywords were determined by
qualitative examination of review papers identified by general keyword search. We only
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included papers that contributed novel information related to mechanisms not described in
prior manuscripts that we had included, which was determined by review of the potential
manuscript by the primary author MR. As noted by our keyword selection, we examined
both MDD and depressive symptomatology. We choose to focus on non-genetic mechanistic
factors given the inability to cover both genetic and other mechanistic factors in only one
review. Lastly, we would emphasize to readers that concepts have necessarily been reduced
to general key points given the intrinsic complexity of the referenced subjects and the wide
breadth of information.
3. Evidence for bidirectional causal relationship between cytokine

activation and depression
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As described earlier, evidence exists explaining contribution of depression to cytokine

elevation, contribution of cytokine elevation to depression, and bidirectional interaction
of cytokine activation and depression, with respect to cytokines both in the periphery and
the CNS. Of note, peripheral cytokine elevations in depression are subclinical, typically
presenting without constituent symptoms of high-grade inflammation (e.g. fever) and lower
than peripheral cytokine elevations in immune or pathogenic illnesses.
In terms of cross-sectional evidence suggesting depression is associated with cytokine

elevation, several meta-analyses confirm elevations of cytokines in peripheral circulation
in patients with MDD compared to healthy controls, including elevated plasma interleukin-6
(IL-6), C-reactive protein (CRP)/high-sensitivity CRP (which detects lower levels of CRP),
and tumor-necrosis-factor-alpha (TNFα) (Dowlati et al., 2010). Additionally, less robust
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evidence demonstrates elevations in plasma soluble IL-2R, IL-1β, IL-10, and IL-1 receptor
antagonist (IL-1RA) (Howren et al., 2009; Köhler et al., 2018; Yuan et al., 2019).
Concordantly, clinical cerebrospinal fluid (CSF) and brain autopsy studies in depressed and
suicidal individuals identify elevations in IL-1β, IL-6, and TNFα as being associated with
depressive symptomatology, although some mixed findings and small samples characterize
these studies (Carpenter et al., 2004; Dean et al., 2010; Felger et al., 2018; Levine et al.,
1999; Pandey et al., 2012; Sasayama et al., 2013; Tonelli et al., 2008). Most patients with
MDD do not show frank signs of clinical infection, such as fever or elevations in white
blood cell counts, suggesting lack of an exogenous source of cytokine activation. Taken
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together, these findings suggest that depressive symptomatology contributes to immune

system activation.
The research evidence also shows that inflammation and peripheral cytokine activation
are associated with and contribute to depressive symptomatology, based on cross-sectional
studies and studies of individuals with comorbid medical illnesses. Models in rats and mice
show that depressive symptoms develop following the administration of lipopolysaccharide
or other inflammatory stimuli (Shen et al., 1999). In humans, cytokine treatments (e.g.
interferon alpha (IFNα) or IL-2) for certain illnesses, bacterial infection, viral infection,
and vaccines have all been associated with cytokine-mediated induction of depressive
symptoms (Capuron et al., 2001). Similarly, high comorbidity of autoimmune diseases
and depression have suggested a role of peripheral and central cytokines in depression,
with general identification of IL-1β, IL-6, and TNFα as key participants (Dantzer et al.,
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2008; Kubera et al., 2011; Raison et al., 2006). Meanwhile, in individuals with comorbid
medical illness, anti-inflammatory treatments such as nonsteroidal anti-inflammatory drugs
(NSAIDs), statins, and cytokine inhibitors are associated with reduction in depressive
symptoms, often independently of improvement in comorbid medical illness (Kappelmann
et al., 2018; Köhler et al., 2014; Salagre et al., 2016). These findings suggest that immune
system activation may lead to depressive symptomology.
To further bolster the findings of cross-sectional studies, longitudinal clinical studies

identify a bidirectional relationship of depression and immune system alterations (primarily
peripheral) in depressed individuals, generally within timeframes between a few months to
less than five years. One meta-analysis and a few large cohort studies suggest that increases
in peripheral inflammatory indices (primarily CRP, IL-6, and IL-8) precede depressive
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symptomatology, while one smaller study implicated CSF IL-1β in the development of
depression (Baune et al., 2012b; Gimeno et al., 2009; Khandaker et al., 2014; Lamers
et al., 2019; Milaneschi et al., 2009; Miller et al., 2019; Smith et al., 2018; Valkanova
et al., 2013). For instance, findings from the Dunedin cohort demonstrated that elevated
serum IL-6 in childhood was associated with depression in early adulthood (Khandaker et
al., 2014). Suggesting that depressive symptoms contribute to pro-inflammatory cytokine
activation, other studies find that general reduction of depressive symptoms leads to a
reduction in peripheral inflammatory markers, or that depressive symptoms predict future
peripheral IL-6, CRP or other cytokine elevation (Supplemental Table 2) (Dahl et al.,
2016; Glaus et al., 2018; Stewart et al., 2009). Moreover, consistent with these findings
which demonstrate a bidirectional relationship between inflammation and depression, a
recent meta-analysis identified that elevated CRP and IL-6 (measured via saliva, blood
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or lumbar puncture) predicted higher future depressive symptoms, and vice versa (Mac
Giollabhui et al., 2020). In terms of individual studies examining bidirectional relationships,
a study of depression following IFNα treatment used time-lagged analyses to show that
elevated peripheral IL-6 predicted increased depressive symptomatology and vice versa
(Prather et al., 2009). Similarly, a recent smaller study examining male twins found
that elevated plasma IL-6 predicted future depressive symptomatology, while elevated
depressive symptoms prospectively predicted elevated plasma CRP levels (Huang et al.,
2018). Together, the limited research suggests that depressive symptomatology leads to
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elevations in cytokines, and vice versa, at least in the short term.
4. Mechanisms for cytokine mediated depression: cytokine activation

leading to depression
4.1. Overview
The most prominent mechanisms for cytokine-induced depression involve neurotransmitter
alterations, disruption of neurogenesis, hypothalamic pituitary axis activation, kynurenine
pathway activation, and the gut-brain axis (Felger and Lotrich, 2013; Jeon and Kim, 2016).
We will examine the evidence for each of these mechanisms, at the theoretical, molecular,
preclinical, and clinical level (Felger and Lotrich, 2013).
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4.2. Neurotransmitter alterations

CNS neurotransmitter alterations are well studied in MDD, with ongoing debate focused
on the relative primacy and contributions of various neurotransmitters alterations in
depression, including low synaptic monoamines (Capuron and Miller, 2011). Lower synaptic
levels of serotonin, dopamine, norepinephrine, and gamma-aminobutyric acid (GABA)
and higher levels of glutamate are likely present in certain regions of the CNS of
depressed patients. Effects of cytokines (prominently IL-1β, TNFα, IFNα, or IL-6) on
neurotransmitter alterations have primarily been demonstrated in in-vitro models, murine
models, and models with exogenous immune stimulus administration (Felger and Lotrich,
2013; Miller et al., 2013). In these studies, proinflammatory cytokines have been shown to
reduce monoamine synaptic activity, increase monoamine reuptake, or decrease monoamine
release (Supplemental Figure 1) (Hodes et al., 2015; Miller et al., 2013). Indirectly, they
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may affect monoamine activity via several mechanisms including monoamine pathway
cofactors (e.g. tetrahydrobiopterin, BH4), direct enzymatic effects, modulation of the
vagal nerve, or oxidative stress (Miller et al., 2013; Miller et al., 2009). Specifically,
IL-1β, IFNα, and TNFα can increase activity of monoamine enzymes, such as the
serotonin reuptake transporter enzyme (SERT) (Zhu et al., 2006). Similarly, IFNα has
been implicated in extracellular dopamine regulation (Felger and Lotrich, 2013). These
cytokine-induced monoamine alterations may occur in depression-relevant brain regions
such as the hippocampus, hypothalamus, and prefrontal cortex (PFC) (Zalcman et al., 1994).
For instance, one clinical study of patients treated with IFNα found a negative correlation
between CSF 5-Hydroxyindoleacetic acid (5-HIAA) and CSF IL-6 (Raison et al., 2009).
However, a recent post-hoc study of treatment-resistant MDD patients found no association
between plasma IL-6 and CSF monoamine metabolites or BH4, suggesting further research
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is warranted (Rengasamy et al., 2018).
Apart from the monoamine pathway, cytokines (primarily TNFα, IL-1, IL-6, and IL-18)
have been associated with changes in glutamate signaling (Supplemental Figure 2), via
enzymatic effects and the kynurenine pathway (described later) (Haroon and Miller, 2016).
These changes include effects on glutamate release, glutamate reuptake, and enhancement
of signal transducers of glutamate receptors (Haroon and Miller, 2016). For example, TNFα
may increase glutamate release by microglia through upregulation of glutaminase (which
converts glutamine to glutamate) and to block astroglial reuptake of glutamate, leading

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to glutamate-mediated neurotoxicity (Takeuchi et al., 2006). Similarly, in neurons, IL-1β

was shown to activate tyrosine kinase to enhance NMDA-glutamate-mediated neurotoxicity
(Viviani et al., 2003). Concurrently, some cytokines (e.g. TNFα) may reduce the anti-
excitatory neurotransmitter GABA’s activity via GABA receptor endocytosis, thereby
upgregulating glutamate activity (Stellwagen et al., 2005). However, this relationship with
glutamate is not consistent, as IL-1β may potentially enhance GABA receptor function
via ion channel activation (Miller et al., 1991; Vezzani and Viviani, 2015). IL-6 has been
associated with decreases in both glutamate and GABA signaling via both direct receptor
effects and reduction of GABA cell populations (Dugan et al., 2009; Vezzani and Viviani,
2015). Cytokines (primarily IL-1β) also limit effects of cannabinoid receptors, which are
involved in blockade of cytokine effects on other neurotransmitter receptors and reduction of
excitotoxicity (Vezzani and Viviani, 2015). Clearly, cytokine effects on neurotransmitter
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activity exist but the mechanisms by which they occur are complex, requiring further
specificity to identify state and region-specific effects.
4.3. Dysfunctional neurogenesis

Dysfunctional neurogenesis at the molecular level, particularly in the hippocampus, has
been associated with depressive-like behaviors in animal models with potential cytokine
involvement (Krishnan and Nestler, 2008). Notably, proinflammatory cytokine (e.g. IL-6)
activation has been associated with both decreases in neurogenesis and increases in
neurogenesis, with effects partially dependent on the temporality of activation and level
of cytokine elevation (Erta et al., 2012). Two factors implicated in cytokine-related
dysfunctional neurogenesis are apoptosis and neurotrophic factors deficits (Supplemental
Figure 3). IL-1β and TNFα have been associated with decreased neurogenesis via activation
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of apoptotic pathways or reduction of cell differentiation into neurons (Kohman and Rhodes,
2013), generally in murine or progenitor cell models (Borsini et al., 2015; Downen et
al., 1999). Regarding neurotrophic factors, brain-derived neurotrophic factor (BDNF) is a
neurotrophic factor present in the hippocampus, and deficits of BDNF have been associated
with depressive symptomatology (Molendijk et al., 2014). Some cytokines, such as IL-1β,
have been associated with reduction in hippocampal BDNF mRNA expression in a murine
studies (Numakawa et al., 2014). Early clinical studies do not bear out such associations,
finding positive associations of plasma IL-6 with BDNF and null/positive relationship of
TNFα and BDNF (Neupane et al., 2015; Patas et al., 2014), suggesting the need for
future clinical studies to help understand the reasons for differences between clinical and
preclinical studies.
4.4. Neuroanatomical and neurocircuitry alterations

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In conjunction with effects on neurotransmitters and neurogenesis, peripheral cytokine

activation has been associated with abnormalities in certain brain regions, neural circuits,
and neural networks. Meta-analyses find that patients with MDD have reductions in
volumes of their hippocampus, anterior cingulate cortex (ACC), and orbitofrontal cortex,
with less replicated findings for volumetric reduction of the basal ganglia and amygdala
(Hamilton et al., 2008; Lorenzetti et al., 2009; Schmaal et al., 2016; Wise et al.,
2017). Consistently, studies in depressed individuals suggest associations of increased
pro-inflammatory cytokines (e.g. IL-6, TNFα) with smaller hippocampal volume (Baune
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et al., 2012a; Frodl and Amico, 2014). Additionally, peripheral cytokines such as IL-6
are implicated in development of white matter hyperintensities (WMH), which indicate
demyelination or white matter loss and are associated with depressive symptomology
(Herrmann et al., 2008; Satizabal et al., 2012). Ischemic lesions in the white matter (along
with WMH), potentially due to downstream effects of cytokine activation through effects on
vascular homeostasis, are also theorized to contribute to depressive symptoms as described
in the vascular depression hypothesis (Taylor et al., 2013). Lastly, pre-clinical models
suggest that cytokine effects may lead to structural breakdown of the blood brain barrier
(BBB) (Banks, 2005). This BBB breakdown may lead to increased cytokine presence in
the brain, particularly in regions controlling mood and emotion. However, no robust clinical
evidence exists demonstrating evidence of BBB breakdown in conditions of low-grade
inflammation.
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In regards to brain activation patterns, a recent fMRI meta-analysis found activations of

limbic (amygdala, hippocampus, hypothalamus), striatal, brainstem, and cortical (e.g. dorsal
anterior cingulate cortex (dACC), dorsomedial prefrontal cortex (dmPFC)) regions that were
associated with peripheral inflammation, including cytokines such as IL-1β, IL-6, IL-1RA,
or soluble TNFαR2 (Kraynak et al., 2018). Cytokines such as IL-1 may cross the blood-
brain barrier to activate neurons in brain regions central to depression, such as the amygdala
(Konsman et al., 2002). Given the concordance in inflammatory and depression-associated
brain regions, inflammation may lead to these changes in functional brain activation, as
seen in studies implicating the dACC, ventral striatum, and subgenual ACC (sgACC) in
mediating IL-6 or TNFαR2 associated mood changes (Frodl and Amico, 2014).
In depression, neurocircuitry changes are also characterized by different connections

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between areas of the brain as compared to healthy controls (Kaiser et al., 2015). These
neurocircuitry changes are associated with difficulty with emotional regulation and other
symptoms characterizing and preceding depression. For instance, individuals with MDD
may have abnormalities in the connections of the limbic-medial prefrontal circuit, leading to
a decrease in medial prefrontal cortical activity and excess amygdala activation (Price and
Drevets, 2010). Increased plasma CRP, a marker of cytokine activation, similarly has been
associated with decreased amygdala-ventromedial PFC connectivity (Mehta et al., 2018).
Two neurocircuits associated with cytokine activation, largely on a theoretical basis, are the
default mode network (DMN) and reward circuit, described below. However, other studies in
non-depressed populations suggest peripheral cytokine associations (IL-6, IFNα) with motor
neurocircuitry (Miller et al., 2013).
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Reward circuits involve projections of dopamine neurons from the ventral tegmental area to
the ventral striatum and nucleus accumbens. Pro-inflammatory cytokines (e.g. IL-6, IFNα,
TNFα) may act through mechanisms including kynurenine pathway activation, reduction in
dopamine neurotransmission, or direct neurotoxicity as in the case of IL-1 RA (Swardfager
et al., 2016) to disrupt reward circuitry. For instance, one study in depressed patients found
that increased peripheral CRP, IL-6, IL-1β, and IL-1RA were associated with decreased
striatal-ventromedial PFC connectivity, a component of the reward pathway (Felger et
al., 2016). Animal and human studies suggest these alterations of reward circuitry that
follow activation of inflammatory processes results in symptoms of anhedonia. In another

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study, increased plasma CRP (in conjunction with basal ganglia glutamate) was associated
with increased anhedonia in depressed patients, with association of anhedonia and reward
processing regions (Haroon et al., 2018). Ultimately, cytokine-induced anhedonia may
progressively lead to other symptoms of depression.
The DMN is theoretically associated with rumination or attention deficits in depression,

and has primary nodes in the posterior cingulate cortex and ventromedial PFC (Hamilton
et al., 2015). One study in healthy adults found that plasma IL-6 was associated positively
with sgACC connectivity in the DMN and negatively with dmPFC connectivity in the DMN
(Marsland et al., 2017a). Similarly, lipopolysaccharide-induced elevations of plasma IL-6 in
healthy humans has been associated with increased connectivity between the left thalamus
and right posterior cingulate cortex (Labrenz et al., 2016). Thus, cytokine effects may induce
changes in the DMN that relate to depressive symptoms.
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Although the extant research has identified associations with both the DMN and reward
pathways with cytokines in depression, forthcoming studies are needed help identify if such
findings are specific to these pathways and the mechanism of action of such pathways.
4.5. Hypothalamus pituitary adrenal (HPA) axis activation

Overactivation of the HPA axis has been demonstrated in depressed patients for many
years, consistent with significantly elevated rates of depression in hypercortisolemic
states such as Cushing’s disease (Pariante and Lightman, 2008; Sonino and Fava, 1998).
The HPA axis involves the hypothalamus, which produces cortisol releasing hormone
(CRH), which then interacts with pituitary cells to release adrenocorticotrophic hormone
(ACTH), which stimulates cortisol production in the adrenal glands (Pariante and Lightman,
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2008). In depression, numerous studies demonstrate abnormal dexamethasone cortisol

response (e.g. decreased suppression of cortisol after administration of dexamethasone)
or hypercortisolemia (Stetler and Miller, 2011). However, these findings are not consistent
in all depressed patients and may vary depending on factors such as cortisol source, age,
gender, type of depression, severity of depression, or history of trauma (Burke et al., 2005;
Knorr et al., 2010; Kunugi et al., 2015; Pariante and Lightman, 2008; Zorn et al., 2017).
As demonstrated primarily in murine and in vitro models, cytokines such as IL-6 and IL-1β
centrally activate the hypothalamus, likely at parvocellular paraventricular cortisol-releasing
hormone (PVN-CRH) neurons (Bethin et al., 2000; Ferri and Ferguson, 2003). Cytokine
effects at PVN-CRH neurons may be mediated via a transcriptional effects at the CRH
gene, intermediary reactive oxygen species, or activation of pathways involved in neuronal
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depolarization (Schrader et al., 2006; Shi et al., 2010; Vallières and Rivest, 1999). Via PVN-
CRH neuron release of CRH and CRH-mediated ACTH release at the median eminence of
the pituitary, cortisol is ultimately released from the adrenal cortex. Concurrently, cytokines
such as IL-1β and IL-6 activate the transcription factor nuclear factor kappa beta (NF-kβ) in
a variety of cell types including macrophages (Miller et al., 2009). Such activation leads to
reduction of glucocorticoid receptor mRNA production, increase in the inert glucocorticoid-
binding glucocorticoid receptor beta (GR-β), and disruption of activated glucocorticoid
receptor function via translocation blockade and direct protein-protein interactions (Pace and
Miller, 2009; Pariante et al., 1999). These changes to glucocorticoid effects on certain cell
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types may limit negative feedback of cortisol on the HPA axis. Given that the hippocampus
provides negative feedback to the HPA axis, cytokine-mediated hippocampal damage may
result in further activation of the HPA axis (Schloesser et al., 2009). Overall, the theoretical
and preclinical evidence indicates that cytokine activation leads to HPA axis activation
(Supplemental Figure 4) (Kim et al., 2016).
In depressed patients, various cortisol measures (e.g. plasma cortisol) demonstrate either
no association between plasma cytokines (e.g. IL-1 and IL-2) or positive association
with cytokines (e.g. IL-6) (Anisman et al., 1999; Kaestner et al., 2005; Karlovic et al.,
2012; Wichers et al., 2007). Such varied results may be due to multiple issues in the
reliable measurement of cortisol levels, lack of robust methodology, depression subtype
heterogeneity, or the cross-sectional nature of such analyses. Thus, the existing clinical
research does not demonstrate a clear association between cytokines and HPA axis activation
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in depression, despite evidence of acute cytokine-induced HPA axis activation and increased
cytokine activity secondary to cortisol resistance. Upcoming research should clarify these
results in clinical samples using more robust methodology, particularly focusing on the
temporality of cytokine and HPA axis changes in relation to depressive symptoms.
4.6. Kynurenine pathway activation

More recently implicated in depressive pathology, the kynurenine pathway involves the
degradation of tryptophan into kynurenine (Supplemental Figure 5). Kynurenine accounts
for greater than 90% of tryptophan breakdown products, with serotonin being the other
tryptophan metabolite (Badawy, 2017). Tryptophan and kynurenine are transported across
the blood-brain barrier, with about 40% of CNS kynurenine produced from CNS tryptophan
(Badawy, 2017; Cuartero et al., 2016; Fukui et al., 1991). Kynurenine then is converted
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into kynurenic acid and quinolinic acid. This conversion primarily occurs in the CNS by
indoleamine 2,3-dioxygenase (IDO) and peripherally by tryptophan 2,3-dioxygenase (TDO),
with greater activation of IDO under times of significant inflammatory activation. IDO is
induced by cytokines (most prominently IFNγ but also IFNα, IL-1β, IL-6, and TNFα) and
inhibited by nitric oxide, anti-inflammatory cytokines (e.g. IL-10, IL-4), and tryptophan.
In states without significant inflammatory activation, TDO is not induced by cytokines
but rather is induced by cortisol, heme cofactors, and nicotinamide adenine dinucleotide
phosphate (NADP) (Badawy, 2017).
Theoretically, kynurenine (KYN) may be converted preferentially into the neurotoxic

NMDA-glutamate agonist quinolinic acid (QA) as opposed to the neuroprotective NMDA
glutamate antagonist kynurenic acid (KA). Excess QA activation of NMDA receptors
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may lead to cell death in depression-relevant brain regions via calcium mediated toxicity,
failure of synaptogenesis via mechanistic target of rapamycin (mTOR) or BDNF pathways
(Supplemental Figure 6) (Zanos and Gould, 2018). KA also acts as an alpha 7 nicotinic
acetylcholine receptor (α7nAChR) antagonist (Badawy, 2017). Antagonism of α7nAChR
has shown direct antidepressant properties in murine models, while pharmacological
blockade of nicotinic acetylcholine receptors has decreased depressive symptoms in humans
in small preliminary clinical studies, suggesting another neuroprotective mechanism for KA
(Philip et al., 2010). Other kynurenine pathway metabolites such as 3-hydroxykynurenine

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and picolinic acid may affect ATP synthesis or induce oxidative stress and consequently
reduce neuronal survival in depression-relevant brain regions (Réus et al., 2015). Cytokines
(e.g. IL-6 or TNFα) mediate IDO activation in a number of suggested brain regions,
including the hippocampus (Réus et al., 2015). Preliminary findings in humans suggest that
kynurenine pathway activation may reduce volumes of the hippocampus or prefrontal cortex
(Meier et al., 2015a; Meier et al., 2015b). Lastly, a few studies demonstrate that kynurenine
pathway activation has effects on oxidative stress and dopamine regulation (Miller et al.,
2009).
Although stimuli-induced cytokine activation (e.g. IFNα) in depressed patients and pre-
clinical models has been shown to result in peripheral kynurenine pathway activation,
a recent meta-analysis surprisingly found decreased kynurenine pathway activation (e.g.
decreased KA and KYN measured in blood, urine, CSF, or brain tissue) in depressed
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patients compared to healthy controls, although antidepressant-free depressed patients had

elevated QA levels compared to controls and blood levels of QA were elevated in depressed
patients compared to controls(O’connor et al., 2009; Ogyu et al., 2018). However, some of
these conflicting findings may be explained by differential regulation of peripheral TDO
from central IDO or differential brain-region regulation of the kynurenine pathway (Chen
et al., 2017). In fact, studies of CSF in suicidal and depressed patients more consistently
find elevations of QA, suggesting the kynurenine pathway may be more validly studied in
the CSF (Bryleva and Brundin, 2017; Raison et al., 2010). These studies typically do not
demonstrate reduction in CNS tryptophan and serotonin concentrations with kynurenine
pathway activation, consistent with studies showing dichotomy of kynurenine pathway
activation and CNS tryptophan depletion (Hughes et al., 2012; Raison et al., 2010; Wichers
et al., 2005). Thus, despite excellent pre-clinical and stimuli-induced models of kynurenine
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pathway activation in depression, clinical studies of the peripheral kynurenine pathway

activation have yet to fully bear this out, and further studies are required to confirm results
from CSF kynurenine pathway studies.
4.7. Gut-brain axis activation and the microbiota

The gut microbiota is a dynamic intestinal reservoir of 1000+ bacterial species. Some
microbiota species have positive effects on health, while others are maladaptive (Rooks and
Garrett, 2016). A putative “gut-brain axis” exists, wherein alterations in gut microbiota are
linked to changes in behavior due to central nervous system effects (Foster and Neufeld,
2013). Evidence for gut-brain axis activity in depression is largely pre-clinical, though a few
clinical studies exist. Mice with absence of gut microbiota, termed “germ free mice,” have
abnormal stress responses, decreased central BDNF levels, differential central monoamine
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metabolism, impairments in microglia activity, myelin protein dysregulation, and alterations

of cytokines such as IL-1 and IL-6 (Hoban et al., 2015; Liu et al., 2016; Sherwin et al.,
2016). Similarly, probiotic administration reduces depressive symptomatology in murine
models, while vagotomy eliminates these beneficial effects (Foster and Neufeld, 2013).
In depressed humans, clinical studies have found depressive symptoms associated with
presence of certain gut bacterial species such as Enterobacteriaceae (Jiang et al., 2015;
Naseribafrouei et al., 2014). In RCTs and observational studies in humans, preliminary
findings of efficacy of antidepressants for bacterial infections, efficacy of antibiotics for

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depression, and efficacy of probiotics for depression also hint that microbiota have a role in
clinical depression (Huang et al., 2016; Macedo et al., 2017).
In murine and primate models, both acute and chronic stress lead to alterations in the
microbiota diversity and increase leakiness of the intestinal wall (Cryan and Dinan, 2012;
Foster and Neufeld, 2013; Sherwin et al., 2016). Then, this gut microbiota dysbiosis
leads to alteration-specific changes in bacterial species that may cause different changes
in immune cell populations, such as Th17 or regulatory T cells (Treg), and results in
variations in microbiota metabolites (Rooks and Garrett, 2016). Such changes in gut immune
cell populations may lead to systemic pro-inflammatory cytokine activation, including
IFNγ and TNFα, and vice versa (Rooks and Garrett, 2016). Microbiota metabolites
include neurotransmitters (e.g. 5-HT or tryptophan) and short chain fatty acids, and these
metabolites activate enteroendocrine cells in the gut, which interact directly with vagal
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afferents via serotonin 5-HT3 receptors (Bonaz et al., 2018; Morrison and Preston, 2016).
Vagal afferent fibers project to the nucleus tractus solitarus (NTS) in the brainstem and
its downstream projections such as the hypothalamus and amygdala (Bonaz et al., 2018).
Ultimately, signals from vagal afferents may translate into depressive behavior and cytokine
release through effects on the HPA axis (via the hypothalamus) or fronto-limbic circuitry
(via the amygdala). Effects of microbiota metabolites on tryptophan catabolism may also
influence depressive symptomatology via the aforementioned kynurenine pathway.
One smaller quasi-clinical study found decreases in microbiome diversity in rats with
transplanted fecal microbiota from depressed human patients, although there were no
changes in rat plasma cytokine levels after transplantation (Kelly et al., 2016). One larger
clinical study and several preclinical studies suggest increases in gut permeability and
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bacterial translocation based on peripheral immunoglobulin levels against gut bacteria in

depressed patients, although studies have not examined direct effects on cytokines (Maes
et al., 2012). Thus, based primarily on preclinical and theoretical evidence, microbiota
dysbiosis may lead to effects on other putative mechanistic pathways involved in cytokine
activation (e.g. HPA axis) via microbiota metabolites or lead to direct effects on cytokine
expression. Forthcoming research should examine temporal associations of microbiota
dysbiosis and cytokine changes in clinical samples, and ultimately if these are reflected
in clinical samples.
4.8. Reactive oxygen species (ROS) and reactive nitrogen species (RNS)
Reactive Oxygen Species (ROS; O2−, OH− ) and Reactive Nitrogen Species (RNS) are
short-lived molecules that are involved in numerous cell death pathways, and are commonly
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released by macrophages via inducible nitric oxide synthase (iNOS) activation, cytokine
signals, and other cell death signals (Predonzani et al., 2015; Redza-Dutordoir and Averill-
Bates, 2016). ROS and RNS can directly lead to cell death through damage to cell
proteins, mitochondrial damage, damage to DNA, axonal damage, endoplasmic reticulum
stress protein damage, or lipid peroxidation (Redza-Dutordoir and Averill-Bates, 2016).
Meta-analyses have found that peripheral markers of oxidative damage are elevated in
depressed patients, particularly 8-hydroxy-2’-deoxyguanosine, malondialdehyde (MDA),
and F2-isoprostanes (Black et al., 2015; Lopresti et al., 2014). Concurrently, depressed
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patients have been found to have a lower anti-oxidant “status” (e.g. having lower levels of
anti-oxidants such as zinc) that reflects higher levels of systemic ROS (Palta et al., 2014;
Swardfager et al., 2013).
RNS/ROS are bidirectionally associated with cytokine activation at a molecular level.

Cytokines such as TNFα, INFγ, and IL-1 may directly interfere with the electron transport
chain, induce iNOS or induce other pro-oxidant enzymes via NF-kβ activation (Chao et al.,
1996; Iborra et al., 2011; Papageorgiou et al., 2016). Additionally, TNFα binds to TNFαR1,
which activates the enzyme NAPDH Oxidase (NOX) through protein-protein interactions,
resulting in direct production of ROS (Blaser et al., 2016). Alternatively, oxidation may
induce the kynurenine pathway via direct activation of IDO, serotonin receptors, or NF-kβ
(Bakunina et al., 2015). Damage associated molecular pattern molecules (DAMPs) are
intracellular proteins that are activated via the RNS/ROS damaging effects on proteins
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and cells, leading to cytokine activation when detected by macrophages. Some pre-clinical
studies have found mice with knockout of antioxidant-associated genes (e.g. Nrf2) have
both increased depressive symptoms and peripheral cytokine activation (e.g. TNFα, IL-6,
IL-10) while administration of certain anti-inflammatory agents in rats results in decreased
depressive symptoms, increased antioxidant parameters, and decreased peripheral cytokine
levels (e.g. TNFα, IL-6) (Thakare et al., 2017; Yao et al., 2016). However, few pre-clinical
or clinical studies have concurrently examined the existence of specific cytokine associations
with oxidative stress markers in depression, with unclear findings in regard to the association
of such cytokines and oxidative stress markers over the course of depression (Lindqvist et
al., 2017; Oglodek et al., 2017).
5 Mechanisms of cytokine induction by depression: where does the

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inflammation come from?

In contrast to the prior section in which we explored mechanisms of cytokine-induced
depression, less clinical evidence exists for the other half of this relationship involving
depression-induced cytokine activation. As described earlier, these connections are likely
multifactorial and not attributable to one cause. We will focus on a few biological
factors given the larger evidence base for these factors, although other behavioral and
medical factors, including obesity, diet, pain, sleep, medical comorbidities, substance
use, and trauma, may be as important (see Supplemental Table 3). One limitation of
the conceptualization of depression as effecting change on cytokine activation is that
depression and cytokine activation are frequently characterized within these literatures as
dual concepts, whereas depression and cytokine activation may be part of a unitary construct
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(Glannon, 2020; Miresco and Kirmayer, 2006). This alternative perspective highlights the
importance of research examining whether casual relationships between depression and
cytokine activation can be identified, e.g., where one variable is manipulated experimentally
and downstream changes in the other are then observed.
5.1. Chronic stress and HPA axis activation

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Chronic stress provides a foundation to understanding the interactions of HPA axis

activation, cytokines and depression, and we summarize this linkage while recognizing
the caveats of simplification of complex neural mechanisms and the incomplete knowledge
base. Stress is broadly defined as a factor resulting in physical or mental tension, and
has been strongly linked with depressive symptomatology (Eisenberger and Cole, 2012;
Raison and Miller, 2013). Generally, the level of stress experienced in response to any
given context or environment may be related to sensory stimuli, ruminative processes,
cognitions, deficits in reward processes, or emotional memory (Belzung et al., 2015; Disner
et al., 2011; LaBar and Cabeza, 2006; Steimer, 2002; Treadway and Zald, 2011). In one
basic hypothesized model of stress, threat detection or stressor presence increases neuronal
activity in the cingulate gyrus, hippocampus, or amygdala and decreases neuronal activity in
the dorsolateral prefrontal cortex (dlPFC) (Disner et al., 2011). In this model of depression,
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chronic activation of these pathways leads to complex remodeling of neural circuitry that
contribute to the changes in mood and cognition that characterize depressive disorders.
While there is evidence that depression results in direct activation of the HPA axis without
mediation via cytokines, acute stress models are also clearly associated with HPA axis
activation and peripheral cytokine elevations (primarily IL-6, IL-10, TNFα, and IL1β)
(Marsland et al., 2017b). Acutely, HPA axis activation may lead anti-inflammatory effects of
the HPA axis’ hormone cortisol which is well known to suppress cytokine activity (Padgett
and Glaser, 2003). However, chronic activation of HPA pathway via the chronic stressors
may lead to the changes in cytokines noted in MDD, with the evidence for this being largely
theoretical and preclinical (Supplemental Figure 7) (Calcia et al., 2016; Marsland et al.,
2017b; Tian et al., 2014).
Established by the described chronic stress-related neurocircuitry changes, PFC,

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hippocampus, and amygdala engagement likely indirectly stimulate hypothalamic PVN cells
(Dedovic et al., 2009). These effects perhaps occur via the bed nucleus stria terminalis
(BNST) and other subcortical brain regions (e.g. dorsomedial hypothalamus and nucleus
tractus solitarius), although limited direct PVN stimulation may be present (Herman,
2012; Jankord and Herman, 2008; Lebow and Chen, 2016). As described previously,
stimulation of the PVN leads to HPA axis activation and cortisol release, which has been
well-characterized in MDD. In MDD, chronic HPA axis activation (secondary to stressors
present in depression) results in hypercortisolemia and glucocorticoid receptor resistance
(Pariante and Miller, 2001). Cortisol is important in suppressing pro-inflammatory cytokine
expression via increasing transcription of anti-inflammatory proteins such as IL-10 and
suppressor of cytokine signaling 1 (SOCS), while blocking transcription of inflammatory
transcription factors such as NF-kβ and activator protein 1 complexes (AP-1) (Desmet and
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De Bosscher, 2017). In the post-translational milieu, glucocorticoids (such as cortisol) also

directly reduce TNFα cytokine mRNA stability and interfere with NF-kβ protein activity
via protein-protein interactions (Desmet and De Bosscher, 2017). With the glucocorticoid
receptor resistance present in MDD, cortisol may fail to have its typical anti-inflammatory
effects on macrophages and other immune cells, leading to cytokine overexpression
in these cells. Notably, contrary to findings of hypercortisolemia in some depressed
individuals, individuals with other subtypes of depression (e.g. atypical depression) have
been hypothesized to have hypocortisolemia, for which the above mechanisms may not be as
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relevant (Lojko and Rybakowski, 2017).
Paradoxically, low but elevated glucocorticoid levels without concurrent glucocorticoid

resistance in certain cells may also lead to increased cytokine activation (Sorrells and
Sapolsky, 2007). Such effects may occur based on the immune cell/cytokine milieu,
neuronal cell type, or level of cortisol elevation. Preclinical studies often find less elevated
levels of glucocorticoids to have stimulatory effects on microglial cells or cytokines
(including IL-1β and macrophage migration inhibitory factor), while more elevated levels
of glucocorticoids tend to be immunosuppressive (Cain and Cidlowski, 2017; Sapolsky et
al., 2000; Tanaka et al., 1997). Additionally, differences in murine models with respect to
glucocorticoid receptor abundance and stress-mediated glucocorticoid receptor production
exist between and within brain regions such as the prefrontal cortex, hippocampus, and
hypothalamus (Mizoguchi et al., 2003; Roque et al., 2016; Zhang et al., 2017). For instance,
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one murine study found that chronic stress resulted in elevations in cytosolic and nuclear
glucocorticoid receptor levels in the hippocampus but only resulted in decreases in cytosolic
glucocorticoid receptors in the prefrontal cortex (Mizoguchi et al., 2003). In regions of
the brain (e.g. hippocampus) with elevated cortisol, glucocorticoid activity may lead to
increased activation of cortisol receptors, followed by activation of endonucleases, DNA
cleavage, failure of protein synthesis, and ultimately cell death (Reagan and McEwen,
1997). Apoptosis and cell death lead to release of DAMPs, which are then recognized
by antigen presenting cells such as macrophages, which subsequently release a variety
of cytokines (Felger and Lotrich, 2013). Such effects are consistent with reports noting
cortisol-mediated hippocampal damage, as previously described.
In summary, hypercortisolemia may lead to cytokine activation (e.g. IL-6 and TNFα) via
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failure of glucocorticoids’ anti-inflammatory activity in certain cells, and overactivity of

glucocorticoids in other cells. As described previously in section 4.5, few clinical studies
have addressed the cytokine-HPA axis interaction which would help clearly delineate this
relationship.
5.2. Stress and sympathetic nervous system activation

As the counterpart to the HPA axis, the sympathetic nervous system (SNS) is the
“fight or flight” part of the nervous system that is activated in response to a stressor,
predominantly releasing norepinephrine and epinephrine. In some hypothesized models
of depression, the chronic prefrontal and limbic neural circuitry changes in depression
(described previously) may activate SNS components including the locus coeruleus in the
brainstem, the hypothalamic paraventricular nucleus, and the rostral ventrolateral medulla
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(rvML) (Aston-Jones and Waterhouse, 2016; Bellinger and Lorton, 2014; Dum et al., 2016).
Sympathetic preganglionic neurons originating from these activated brain regions then may
stimulate spinal cord neurons, which project to the adrenal medulla, leading to adrenal
chromaffin cell release of epinephrine and norepinephrine (Brown et al., 1982; Engeland
and Arnhold, 2005; Morrison and Cao, 2000). Given that clinical studies generally have
not examined the cytokine-SNS relationship in depressed patients, we will primarily review
theoretical and pre-clinical evidence, and future studies should attempt to examine clinical
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associations of SNS activation with cytokine activity.
At both systemic and more localized zones of inflammation, acute activation of the SNS
results in suppression of cytokines such as IL-1β and TNFα via transcription factors
such as NF-kβ in microglia and peripheral macrophages, likely mediated by β2 adrenergic
receptor binding per preclinical models (Hasko and Szab o, 1998; Nance and Sanders,
2007; Scanzano and Cosentino, 2015). However, chronic activation of the SNS may be
associated with β adrenergic mediated transcription of pro-inflammatory cytokines such as
IL-6 (Ramirez et al., 2016; Rohan Walker et al., 2013). Additionally, low level α2 adrenergic
receptor activation (as opposed to greater adrenergic receptor activation) on monocytes or
macrophages is associated with release of certain cytokines (e.g. TNFα) (Chavan et al.,
2017; Pongratz and Straub, 2014).
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The SNS also has indirect effects on the immune system that may predominate over
direct leukocyte adrenergic receptor effects. The SNS may increase peripheral or central
cytokine levels via chronic glucocorticoid release (due to adrenal cortex stimulation) or
vagal nerve hypoactivity (due to downregulation of parasympathetic activity) (Barnes et
al., 2015; Ulrich-Lai and Herman, 2009). Within the SNS, β1 adrenergic receptors on the
renal juxtaglomerular apparatus (JGA) activate the renin-angiotensin system (RAS). RAS
activates ROS/NOS pathways and binding of angiotensin II on AT1 receptors in CNS cells
such as microglia, which results in NF-kβ mediated cytokine transcription (primarily TNFα)
(Labandeira-Garcia et al., 2017). The involvement of this pathway in depression is buoyed
by preliminary observational clinical studies noting efficacy of angiotensin converting
enzyme inhibitors in reducing depressive symptoms (Vian et al., 2017).
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5.3. Vagal nerve hypoactivity

As a key component of the parasympathetic nervous system (PNS), the vagal nerve may also
play a role in cytokine activation in depression. Depressed individuals appear to have altered
parasympathetic activity with possible vagal nerve hypoactivity (Kemp et al., 2010; Marvel
et al., 2004). Vagal nerve hypoactivity may be secondary to direct effects from depression
or from downstream effects of depression activating the SNS, which can suppress the PNS.
Consistent with that hypothesis, vagal nerve stimulation has been suggested as a treatment
for depression, with partial support from clinical trial data (Martin and Martin-Sanchez,
2012).
In recent years, the association between peripheral afferent and efferent vagal nerve
activation and reduction in cytokine production (primarily TNFα) in peripheral organs (e.g.
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liver and spleen) as well as in macrophages, described as the “inflammatory reflex,” has
been elucidated (Supplemental Figure 8) (Tracey, 2002). Concurrent with strong reported
associations between gut pathology and the CNS, afferent vagal nerves in abdominal organs,
the digestive tract, and heart project to the NTS after sensing cytokines (e.g. IL-1) in the
periphery (Johnston and Webster, 2009). Efferent vagal nerves from the NTS project to
the thalamus and the dorsal motor vagal nucleus (DMVN) of the medulla, which also
receives projections from the amygdala and hypothalamus (Yuan and Silberstein, 2016).
The DMVN then projects parasympathetic nerve fibers to a variety of gastrointestinal and
lymphoid organs, including the liver and spleen. These vagal nerve efferents may synapse
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with sympathetic postganglionic noradrenergic nerves in the spleen. In these nerves, splenic
norepinephrine release recruits T cells which then release AcH onto α7nAChR receptors
on macrophages to downregulate cytokine release (Dantzer, 2017). Alternatively, DMVN
derived parasympathetic fibers may send cholinergic signals directly to peripheral organs to
affect circulating monocytes or recruit immunosuppressive T cells. Molecularly, macrophage
α7nAChR receptor activation may lead to phosphorylation and consequent downregulation
of STAT3, which is a major transcription factor for both IL-6 and TNFα (Pavlov and Tracey,
2012).
Such findings are largely supported by research on endotoxemia in murine models, and
extant studies suggest that these pathways are likely present in humans (Dantzer, 2017;
Yuan and Silberstein, 2016). One study found association of parasympathetic dysregulation
and in vitro LPS-stimulated blood cytokine levels of IL-6 and TNFα in healthy controls,
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although other studies of depressed patients suggest both positive and negative covariation of
vagal nerve activity with such peripheral cytokines (Corcoran et al., 2005; Hu et al., 2018;
Marsland et al., 2007). However, more directed studies are needed clinically to examine
naturalistic clinical associations of vagal nerve activity with cytokine changes in depression,
using reliable measures of vagal nerve activity.
5.4. Omega 3 polyunsaturated fatty acid deficits

Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) are natural anti-inflammatory fatty
acids present in foods such as fish and nuts. ω-3 PUFAs include docosahexaenoic acid
(DHA) and eicosapentaenoic acid (EPA). Decreased intake of ω-3 PUFAs in diet may be
secondary to appetite disturbances commonly seen in depression and has been associated
with a higher risk of development of depression (Grosso et al., 2016). In preclinical
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studies, the peripheral anti-inflammatory mechanisms of ω-3 PUFAs are well described,
with theoretically similar effects in the CNS (Supplemental Figure 9). ω-3 PUFAs may
bind to cellular G protein receptors such as G-protein coupled receptor (GPR120), which
blocks NF-kβ and c-Jun N-terminal kinase (JNK) pathways, resulting in a decrease in
canonical NF-kB dependent cytokines (e.g. IL-6 and TNFα) (Calder, 2010; Oh et al.,
2010). Alternatively, ω-3 PUFAs may activate peroxisome proliferator-activated receptors
(PPARs), which bind and inactivate cytokine transcription factors such as NF-kβ, STAT, or
AP-1 (Calder, 2010; Tyagi et al., 2011). Lastly, ω-3 PUFAs upregulate anti-inflammatory
proteins such as resolvins and protectins, which mediate effects potentially via transcription
factors (e.g. NF-kβ) or micro RNA (miRNA) pathways that have demonstrated reduction of
LPS-induced proinflammatory cytokine expression (e.g. IL-6, TNF-α, or IL-1β) (Rey et al.,
2016).
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In a few meta-analyses, ω-3 PUFA supplementation demonstrated beneficial effects as an

adjunctive pharmacologic treatment for MDD, although studies tended to be heterogenous,
smaller, and demonstrated greater benefits for EPA as compared to DHA (Mocking et al.,
2017). Such benefits appear greater for those with elevated cytokine activation. For example,
a recent trial found that in patients with MDD and higher relative levels of IL-1RA and
hs-CRP, individuals experienced greater reductions in depression severity when treated with
ω-3 PUFAs compared to patients with MDD with lower relative levels of plasma IL-1RA
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and hs-CRP (Rapaport et al., 2016). Extant studies in non-depressed populations suggest
that higher plasma ω-3 PUFAs are associated with lower levels of plasma IL-6, IL-1RA,
and TNFα and higher levels of plasma IL-10 (Ferrucci et al., 2006). Although preliminary
clinical observations of depressed patients similarly suggest association of lower ω-3 PUFA
plasma levels with elevations in plasma TNFα and IL-6, studies have not sufficiently
replicated such ω-3 PUFA and pro-inflammatory cytokine associations in depressed cohorts
(Kiecolt-Glaser et al., 2007; Lai et al., 2016).
6. Discussion, areas of future research, and limitations

In summary, cytokine related induction of depressive symptomology may directly occur
due to the effects of cytokines on neurotransmitters, brain regions, or neural networks
(Supplemental Figure 10). Indirectly, cytokines may also activate large physiological
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networks such as the HPA axis and the gut-brain axis to trigger depression pathways.
From a molecular perspective, cytokines may also activate the kynurenine pathway or
ROS/NOS pathways, leading to accumulation of neurotoxic metabolites. At the same time,
depressive symptoms may lead to activation of the HPA axis or SNS overactivity (and
concurrent vagal nerve hypoactivity), which lead to increase in pro-inflammatory cytokine
levels, enhanced by deficits in omega 3 fatty acids. However, other factors associated
with depression, such as obesity, diet, pain, sleep, medical comorbidities, substance use,
and trauma, may play a role in cytokine activation but require more research. The
mechanism with the strongest evidence for cytokine-induced depression likely relates to the
effects of cytokines on neurotransmitters and neural networks; fair preclinical and clinical
evidence exists as well for the role of cytokines on the HPA axis. As one feature in a
multifactorial stress-diathesis model, depressive symptoms may lead to pro-inflammatory
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cytokine activation, which in turn, may contribute to worsening depressive symptoms. In

conjunction, pro-inflammatory cytokine activation may contribute to depressive symptoms
through the described mechanistic pathways.
Although recent research has helped to elucidate the mechanistic interactions between
depression and cytokine activation, important areas of future research exist. First,
methodologically robust clinical research examining these mechanisms in human
populations is needed, given that clinical depression is typically heterogeneous, episodic,
and not always treatment-responsive, as compared to preclinical models. Given the
heterogeneity of depression, multiple mechanisms may be contributing to cytokine
involvement in depression. Noting the numerous pre-clinical studies and relative dearth
of large cross-sectional or longitudinal clinical studies, future studies would best focus on
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clinical populations with careful attention to the weight of various moderating factors on
cytokine activation and specificity of different cytokines. Long term clinical research could
identify aberrations in inflammatory/cytokine networks in depressed individuals, rather than
just individual cytokine levels, given that cytokines are constantly interacting with each
other and other parts of the immune system. Ultimately, such research could help guide
identification of treatments for depression. Further exploration is required to investigate
modulating factors of cytokine activity in depression, including unique cytokine effects,
duration of cytokine alterations, cellular targets of cytokines, and brain region-dependent
variations in cytokine effects. Clarification of the time, cell and location dependent effects of
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cytokines is critical to recognizing moderating factors of cytokine activation. Given cytokine

alterations reported in other psychiatric disorders such as schizophrenia and autism, better
understanding of depression-specific cytokine associations is also needed. As previously
described, an important critique of the conceptualization in contemporary frameworks of
depression and cytokine activation is that they are dualistic in nature. If biological and
psychological aspects of depression are part of a unitary construct experienced by some
humans (Glannon, 2020; Miresco and Kirmayer, 2006), then any debate regarding which is
cause and which is effect is nonsensical and can’t be resolved.
7. Conclusions
As the inflammatory hypothesis of depression approaches its 30th anniversary, the
importance of understanding the contribution of cytokines to depressive symptomology
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continues to grow. Researchers have concretely identified elevations of plasma IL-6, CRP,
and TNFα in depressed patients as compared to healthy patients, and the relationship
between cytokines and depression appears to be bidirectional. As described, numerous
mechanisms exist that may mediate interactions between depression and cytokine activation.
Next steps for future research involve methodologically rigorous observational studies and
clinical trials examining these relationships in close detail with attention to confounders and
focusing on the specificity of cytokine effects.
Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
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A Chicken and Egg Scenario in Psychoneuroimmunology - Bidirectional Mechanisms Linking Cytokines and Depression

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A chicken and egg scenario in psychoneuroimmunology:

cUniversity of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

general (e.g. “cytokine”) and topic-specific (e.g. “kynurenine”) keywords.

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Cytokines; Depression; Major depressive disorder; Inflammation; Interleukin-6;

The “inflammatory” hypothesis of depression has received increasing attention in recent

aspects simultaneously (Glannon, 2020; Miresco and Kirmayer, 2006).

3. Evidence for bidirectional causal relationship between cytokine

As described earlier, evidence exists explaining contribution of depression to cytokine

In terms of cross-sectional evidence suggesting depression is associated with cytokine

together, these findings suggest that depressive symptomatology contributes to immune

To further bolster the findings of cross-sectional studies, longitudinal clinical studies

elevations in cytokines, and vice versa, at least in the short term.

4. Mechanisms for cytokine mediated depression: cytokine activation

4.2. Neurotransmitter alterations

is warranted (Rengasamy et al., 2018).

converts glutamine to glutamate) and to block astroglial reuptake of glutamate, leading

to glutamate-mediated neurotoxicity (Takeuchi et al., 2006). Similarly, in neurons, IL-1β

4.3. Dysfunctional neurogenesis

4.4. Neuroanatomical and neurocircuitry alterations

In conjunction with effects on neurotransmitters and neurogenesis, peripheral cytokine

In regards to brain activation patterns, a recent fMRI meta-analysis found activations of

In depression, neurocircuitry changes are also characterized by different connections

follow activation of inflammatory processes results in symptoms of anhedonia. In another

The DMN is theoretically associated with rumination or attention deficits in depression,

4.5. Hypothalamus pituitary adrenal (HPA) axis activation

2008). In depression, numerous studies demonstrate abnormal dexamethasone cortisol

4.6. Kynurenine pathway activation

Theoretically, kynurenine (KYN) may be converted preferentially into the neurotoxic

(Philip et al., 2010). Other kynurenine pathway metabolites such as 3-hydroxykynurenine

patients compared to healthy controls, although antidepressant-free depressed patients had

pathway activation in depression, clinical studies of the peripheral kynurenine pathway

4.7. Gut-brain axis activation and the microbiota

metabolism, impairments in microglia activity, myelin protein dysregulation, and alterations

findings of efficacy of antidepressants for bacterial infections, efficacy of antibiotics for

bacterial translocation based on peripheral immunoglobulin levels against gut bacteria in

RNS/ROS are bidirectionally associated with cytokine activation at a molecular level.

5 Mechanisms of cytokine induction by depression: where does the

inflammation come from?

5.1. Chronic stress and HPA axis activation

Chronic stress provides a foundation to understanding the interactions of HPA axis

Established by the described chronic stress-related neurocircuitry changes, PFC,

De Bosscher, 2017). In the post-translational milieu, glucocorticoids (such as cortisol) also

relevant (Lojko and Rybakowski, 2017).

Paradoxically, low but elevated glucocorticoid levels without concurrent glucocorticoid

failure of glucocorticoids’ anti-inflammatory activity in certain cells, and overactivity of

5.2. Stress and sympathetic nervous system activation

associations of SNS activation with cytokine activity.

5.3. Vagal nerve hypoactivity

5.4. Omega 3 polyunsaturated fatty acid deficits

In a few meta-analyses, ω-3 PUFA supplementation demonstrated beneficial effects as an

6. Discussion, areas of future research, and limitations

cytokine activation, which in turn, may contribute to worsening depressive symptoms. In

cytokines is critical to recognizing moderating factors of cytokine activation. Given cytokine

Axis. Front Neurosci 12, 49. [PubMed: 29467611]

for mental illness. Psychopharmacology (Berl.) 233, 1637–1650. [PubMed: 26847047]

1060–1073. [PubMed: 25248805]

activation of neuronal NADPH oxidase. PLoS One 4, e5518. [PubMed: 19436757]

inflammation in depression? Molecular Psychiatry.

Ferrucci L, Cherubini A, Bandinelli S, Bartali B, Corsi A, Lauretani F, Martin A, Andres-Lacueva

inflammatory markers. J. Clin. Endocrinol. Metab 91, 439–446. [PubMed: 16234304]