Elsevier

Journal of Psychiatric Research

Volume 70, November 2015, Pages 18-27
Journal of Psychiatric Research

Review
Dysregulation of the NF-κB pathway as a potential inducer of bipolar disorder

https://doi.org/10.1016/j.jpsychires.2015.08.009Get rights and content

Highlights

  • Bipolar disorder (BD) comprises of high (mania) and low (depression) mood swings.

  • Progression denotes the increase in the frequency and severity of bipolar symptoms.

  • Inflammation explains this progression and its underlie cognitive impairment.

  • Dysregulated NF-κB signaling pathway may be a core characteristic in BD.

Abstract

A century of investigations enhanced our understanding of bipolar disorder although it remains a complex multifactorial disorder with a mostly unknown pathophysiology and etiology. The role of the immune system in this disorder is one of the most controversial topics in genetic psychiatry. Though inflammation has been consistently reported in bipolar patients, it remains unclear how the immunologic process influences the disorder. One of the core components of the immune system is the NF-κB pathway, which plays an essential role in the development of innate and adaptive immunity. Remarkably, the NF-κB pathway received only little attention in bipolar studies, as opposed to studies of related psychiatric disorders where immune dysregulation has been proposed to explain the neurodegeneration in patient conditions. If immune dysregulation can also explains the neurodegeneration in bipolar disorder, it will underscore the role of the immune system in the chronicity and pathophysiology of the disorder and may promote personalized therapeutic strategies. This is the first review to summarize the current knowledge of the pathophysiological functions of NF-κB in bipolar disorder.

Introduction

Bipolar disorder (BD) is a major episodic chronic psychiatric illness with an accelerating course, which comprises of mood swings that range from extreme high (mania) to extreme low (depression) that appear with discrete beginnings and ends, but may appear together. The changes in symptomatology over the course of the illness, sometimes termed progression, is characterized by increases in the frequency and severity of affective episodes over time (Zis et al., 1980, Roy-Byrne et al., 1985, Goodwin, 2002), worsening of long-term outcome (Schneider et al., 2012), reduction in the likelihood of response to appropriate treatment, both biological, such as lithium (Swann et al., 1999), and psychological, such as cognitive-behavioral therapy (Scott et al., 2006), and worsening health-related quality of life (Roshanaei-Moghaddam and Katon, 2009). The chronicity in BD and its possible contribution toward its progression alongside the growing appreciation of the profound interrelationship between the central nervous system (CNS) and immune system suggests that understanding the role of immunity in the pathophysiology of the disorder may help decipher the molecular mechanisms underlying BD.

The immune system is a neuroanatomical area of great interest in BD due to the emotional and neuronal consequences of major shifts from homeostasis. It is well established that BD is characterized by high peripheral levels of pro-inflammatory agents, such as cytokines (mainly interleukins like IL-2, IL-4, and IL-6) (Brietzke et al., 2011, Munkholm et al., 2013), tumor necrosis factors (TNF-α) (Brietzke and Kapczinski, 2008), and chemokines (e.g., CCL24 and CXCL) (Brietzke et al., 2009a). The observed increase in the peripheral pro-inflammation particularly during mood swings led a growing number of authors to propose that ongoing inflammation and related processes like neuronal death (apoptosis) may account for the observations reported in neuroimaging studies, where at least a subset of BD patients exhibit a cortical thickness reduction (Rajkowska et al., 2001, Jung et al., 2011), significant loss of gray and white matter volumes (McDonald et al., 2004, Haznedar et al., 2005, Lyoo et al., 2006), and changes in morphology and integrity of white matter tracts (López-Larson et al., 2002, Connor et al., 2011, Sprooten et al., 2013). The possibility that chronic inflammation leads to structural brain abnormalities and cognitive deficits in BD patients raised hopes that biochemical markers can be utilized to detect the illness at early stages (Jones and Thomsen, 2013) instead of carrying patient interviews and self-report questionnaires, which lack objectivity and biological validation (Frey et al., 2013). Thus far, however, efforts have met with limited success, suggesting that a more thorough understanding of the immunoregulatory mechanisms in BD is necessary.

Like all mammals, the human immune system also consists of a functionally linked group of anatomically disparate tissues and cell types, most of which are subject to rapid turnover. Orchestrating these processes that involve both cell proliferation and apoptosis requires the involvement of complex regulatory systems. One of those system is the Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway, which has received little attention in BD studies, but its abnormal activity has been widely reported in related mental disorders, like schizophrenia (Song et al., 2009), major depression (Kim et al., 2015), and autism (Manzini et al., 2014). This review aims to bridge this knowledge gap by describing the role of NF-κB in BD and addressing key questions regarding the role of the immune system in the pathophysiology of the disorder.

Section snippets

Progression through stages predicts clinical and mental deterioration

In the course of their illness, bipolar patients may endure an increase in the frequency and severity of symptoms from early onset bipolar with “soft” spectrum conditions to later stages where the symptoms become severe (Schneider et al., 2012). Progression in BD was first documented in the pioneering work of Emil Kraepelin. Kraepelin (1921) described in detail the episodic nature of the disorder and its progression, characterized as faster recurrences (shorter intervals between episodes of

Inflammatory abnormalities and cognitive impairment in bipolar patients

To understand why neuroprotective mechanisms fail to account for the progressive decline in mental health, researchers attempted to stereotype common phases over the course of the disorder. This allowed clinicians to conceptualize the disorder as a combination of episodic “stages,” each with a distinct immunologic signature and clinical outcomes that converge towards clinical impairment (Kapczinski et al., 2009, Gama et al., 2013) (Fig. 1), but it remained unclear which biological mechanisms

Pro- and anti-inflammatory cytokines in bipolar

Cytokines are small signaling proteins secreted by immune cells in response to a variety of stimuli. Cytokines mediate crucial cellular functions, such as proliferation, survival, maturation, and neuroplasticity, during innate and adaptive immune responses (Brietzke and Kapczinski, 2008). Under normal physiological conditions, cytokines have beneficial roles (McAfoose and Baune, 2009); however, during excessive and prolonged activation of the immune response, cytokines can also promote several

The role of the NF-κB in innate and adaptive immunity, neuroprotection, and apoptosis

Interestingly, alongside their critical role in the process of alteration in neuroplasticity (Brietzke and Kapczinski, 2008, Potvin et al., 2008), some pro-inflammatory cytokines also stimulate receptors in neurons linked to the activation of NF-κB, a signaling pathway that modulates neuronal excitability and vulnerability to excitotoxicity (Brietzke and Kapczinski, 2008). Unfortunately, the potential molecular or environmental triggers that activate the NF-κB in brain tissue and involved in

Assessing the role of NF-κB in the etiology of bipolar

The NF-κB signaling pathway has been rarely studied in bipolar patients, though investigations centered on cytokines may have indirectly assessed its role by measuring some of its products. Few studies, however, adopted more direct assessment methods. Sun et al. (2001) provided one of the first lines of evidence for the involvement of NF-κB transcription factors in the frontal cortex of bipolar patient brains. The authors carried a serial analysis of gene expression and reverse

Conclusions

This is the first review of the role that the NF-κB signaling pathway plays in the etiology of BD. This review also considered whether dysregulation of this signaling pathway can explain the progression of the disorder, or phrased differently, increases the allostatic load associated with worsening condition in BD patients. While evidence to the involvement of the NF-κB pathway in the etiology of BD is supported only by a handful of studies, multiple studies reported that pro-inflammatory

Contributors

Eran Elhaik constructed the ideas, reviewed the literature, and wrote the manuscript.

Peter Zandi contributed manuscript editing and revisions and checks for accuracy.

Conflicts of interest

The authors declare no conflict of Interest.

References (145)

  • E. Brietzke

    Is there a role for curcumin in the treatment of bipolar disorder?

    Med. Hypotheses

    (2013)
  • E. Brietzke

    Comparison of cytokine levels in depressed, manic and euthymic patients with bipolar disorder

    J. Affect. Disord.

    (2009)
  • M.H. Chen

    Higher risk of developing major depression and bipolar disorder in later life among adolescents with asthma: a nationwide prospective study

    J. Psychiatr. Res.

    (2014)
  • S.H. Choi et al.

    The distinct roles of cyclooxygenase-1 and -2 in neuroinflammation: implications for translational research

    Trends Pharmacol. Sci.

    (2009)
  • C.M. Connor et al.

    White matter neuron alterations in schizophrenia and related disorders

    Int. J. Dev. Neurosci.

    (2011)
  • F. Dickerson

    Additive effects of elevated C-reactive protein and exposure to herpes simplex virus type 1 on cognitive impairment in individuals with schizophrenia

    Schizophr. Res.

    (2012)
  • F. Dickerson

    Elevated C-reactive protein and cognitive deficits in individuals with bipolar disorder

    J. Affect. Disord.

    (2013)
  • B.S. Fernandes

    Brain-derived neurotrophic factor as a state-marker of mood episodes in bipolar disorders: a systematic review and meta-regression analysis

    J. Psychiatr. Res.

    (2011)
  • M. Font-Nieves

    Induction of Cox-2 enzyme and down-regulation of Cox-1 expression by lipopolysaccharide (LPS) control prostaglandin E2 production in astrocytes

    J. Biol. Chem.

    (2012)
  • C.S. Gama

    Staging and neuroprogression in bipolar disorder: a systematic review of the literature

    Rev. Bras. Psiquiatr.

    (2013)
  • M. Gazal

    Neuroprotective and antioxidant effects of curcumin in a ketamine-induced model of mania in rats

    Eur. J. Pharmacol.

    (2014)
  • I. Grande

    Mediators of allostasis and systemic toxicity in bipolar disorder

    Physiol. Behav.

    (2012)
  • F.R. Greten

    NF-κB is a negative regulator of IL-1β secretion as revealed by genetic and pharmacological inhibition of IKKβ

    Cell

    (2007)
  • N.R. Hall et al.

    Stress and immunity in humans: modifying variables

  • M.S. Hayden et al.

    Shared principles in NF-κB signaling

    Cell

    (2008)
  • M.M. Haznedar

    Fronto-thalamo-striatal gray and white matter volumes and anisotropy of their connections in bipolar spectrum illnesses

    Biol. Psychiatry

    (2005)
  • T. Ichiyama

    Sodium valproate inhibits production of TNF-α and IL-6 and activation of NF-κB

    Brain Res.

    (2000)
  • K.A. Jones et al.

    The role of the innate immune system in psychiatric disorders

    Mol. Cell. Neurosci.

    (2013)
  • R.P. Juster et al.

    Allostatic load biomarkers of chronic stress and impact on health and cognition

    Neurosci. Biobehav. Rev.

    (2010)
  • F. Kapczinski

    Allostatic load in bipolar disorder: implications for pathophysiology and treatment

    Neurosci. Biobehav. Rev.

    (2008)
  • F.v. Kapczinski

    The potential use of biomarkers as an adjunctive tool for staging bipolar disorder

    Prog. Neuropsychopharmacol. Biol. Psychiatry

    (2009)
  • M. Karin

    Whipping NF-κB to submission via GADD45 and MKK7

    Cancer Cell.

    (2014)
  • Y.K. Kim

    Imbalance between pro-inflammatory and anti-inflammatory cytokines in bipolar disorder

    J. Affect. Disord.

    (2007)
  • R.W. Kupka

    High rate of autoimmune thyroiditis in bipolar disorder: lack of association with lithium exposure

    Biol. Psychiatry

    (2002)
  • M. Leboyer

    Can bipolar disorder be viewed as a multi-system inflammatory disease?

    J. Affect. Disord.

    (2012)
  • M.P. López-Larson

    Regional prefrontal gray and white matter abnormalities in bipolar disorder

    Biol. Psychiatry

    (2002)
  • M.C. Manzini

    CC2D1A regulates human intellectual and social function as well as NF-κB signaling homeostasis

    Cell Rep.

    (2014)
  • J. McAfoose et al.

    Evidence for a cytokine model of cognitive function

    Neurosci. Biobehav. Rev.

    (2009)
  • B.S. McEwen

    Interacting mediators of allostasis and allostatic load: towards an understanding of resilience in aging

    Metabolism

    (2003)
  • A. Modabbernia

    Cytokine alterations in bipolar disorder: a meta-analysis of 30 studies

    Biol. Psychiatry

    (2013)
  • K. Munkholm et al.

    Cytokines in bipolar disorder: a systematic review and meta-analysis

    J. Affect. Disord.

    (2013)
  • Z.H. Németh

    Lithium induces NF-κB activation and interleukin-8 production in human intestinal epithelial cells

    J. Biol. Chem.

    (2002)
  • S. Nohesara

    DNA hypomethylation of MB-COMT promoter in the DNA derived from saliva in schizophrenia and bipolar disorder

    J. Psychiatr. Res.

    (2011)
  • S.M. O'Brien

    Cytokine profiles in bipolar affective disorder: focus on acutely ill patients

    J. Affect. Disord.

    (2006)
  • H.M. Abdolmaleky

    Hypomethylation of MB-COMT promoter is a major risk factor for schizophrenia and bipolar disorder

    Hum. Mol. Genet.

    (2006)
  • H.M. Abdolmaleky et al.

    Genetics and epigenetics in major psychiatric disorders: dilemmas, achievements, applications, and future scope

    Am. J. Pharmacogenomics

    (2005)
  • A.S. Baldwin

    Control of oncogenesis and cancer therapy resistance by the transcription factor NF-κB

    J. Clin. Invest

    (2001)
  • M. Berk

    Does stage of illness impact treatment response in bipolar disorder? Empirical treatment data and their implication for the staging model and early intervention

    Bipolar Disord.

    (2011)
  • M. Berk

    From neuroprogression to neuroprotection: implications for clinical care

    Med. J. Aust.

    (2010)
  • J.C. Bournat et al.

    Wnt-1 dependent activation of the survival factor NF-κB in PC12 cells

    J. Neurosci. Res.

    (2000)
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