Associate Editor: Peter Holzer
Immune system to brain signaling: Neuropsychopharmacological implications

https://doi.org/10.1016/j.pharmthera.2011.01.014Get rights and content

Abstract

There has been an explosion in our knowledge of the pathways and mechanisms by which the immune system can influence the brain and behavior. In the context of inflammation, pro-inflammatory cytokines can access the central nervous system and interact with a cytokine network in the brain to influence virtually every aspect of brain function relevant to behavior including neurotransmitter metabolism, neuroendocrine function, synaptic plasticity, and neurocircuits that regulate mood, motor activity, motivation, anxiety and alarm. Behavioral consequences of these effects of the immune system on the brain include depression, anxiety, fatigue, psychomotor slowing, anorexia, cognitive dysfunction and sleep impairment; symptoms that overlap with those which characterize neuropsychiatric disorders, especially depression. Pathways that appear to be especially important in immune system effects on the brain include the cytokine signaling molecules, p38 mitogen-activated protein kinase and nuclear factor kappa B; indoleamine 2,3 dioxygenase and its downstream metabolites, kynurenine, quinolinic acid and kynurenic acid; the neurotransmitters, serotonin, dopamine and glutamate; and neurocircuits involving the basal ganglia and anterior cingulate cortex. A series of vulnerability factors including aging and obesity as well as chronic stress also appears to interact with immune to brain signaling to exacerbate immunologic contributions to neuropsychiatric disease. The elucidation of the mechanisms by which the immune system influences behavior yields a host of targets for potential therapeutic development as well as informing strategies for the prevention of neuropsychiatric disease in at risk populations.

Introduction

Reciprocal interactions between the immune system and the brain have attracted considerable attention regarding the role of the immune system in neuropsychiatric diseases especially major depression. During the last several decades, research in the field referred to as “Psychoneuroimmunology” has demonstrated an intricate network of bi-directional relationships between the immune system and the brain. Alterations in immune function have been found in depressed patients with major depression and include early reports of immune suppression (e.g., reduced natural killer cell activity and reduced lymphocyte proliferation) followed by evidence of increased inflammatory activity (e.g., increased circulating levels of inflammatory markers) (Kronfol et al., 1983, Irwin and Gillin, 1987, Maes et al., 1993, Anisman et al., 1999, Zorrilla et al., 2001). Much of the recent interest in the role of the immune system in depression has focused on increased inflammation associated with depression. Pro-inflammatory cytokines, including interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF)-alpha, are released by activated immune cells during the host response to pathogen invasion as well as in the context of tissue injury and psychosocial stress. These soluble factors appear to represent primary mediators of the communication between the immune system and the brain, and not only help orchestrate cellular responses to immune challenge, but also coordinate the behavioral changes that are necessary for recovery. During the course of immune challenge, the release of pro-inflammatory cytokines is usually transient and regulated by anti-inflammatory mechanisms. Consequently, the behavioral effects triggered by the activation of the inflammatory response develop as an adaptative, temporary and controlled reaction of the central nervous system (CNS) to immune signals. Nevertheless, when immune challenge becomes chronic and/or unregulated, as is observed in patients receiving chronic cytokine treatments or those exposed to chronic medical illness and/or stress, the behavioral effects of cytokines and the resultant inflammatory response may contribute to the development of clinically relevant behavioral symptoms and neuropsychiatric diseases, including major depression. These immune-based behavioral disorders, as well as the pathophysiological mechanisms involved will be discussed in this review along with relevant treatment implications.

Section snippets

Sickness behavior

A rich database has been developed that substantiates the capacity of pro-inflammatory cytokines to induce, in addition to fever and activation of the hypothalamic–pituitary–adrenal (HPA) axis, a constellation of behavioral symptoms referred to as sickness behavior (Dantzer, 2001). Sickness behavior is typically associated with the behavioral changes seen in humans and laboratory animals suffering from microbial infections and includes depressive-like behavior, anhedonia, fatigue, psychomotor

How do cytokine signals access the brain?

Cytokines are relatively large molecules that do not freely pass through the blood brain barrier. Nevertheless, data indicate that cytokine signals are able to reach the brain through humoral, neural and cellular pathways (Fig. 2). These pathways are comprised of at least five non-exclusive mechanisms, including 1) passage of cytokines through leaky regions of the blood-brain barrier, including the choroid plexus and circumventricular organs, 2) active transport via saturable cytokine-specific

Pathophysiological mechanisms by which cytokines affect the brain

A number of pathways by which cytokines may influence behavior have been identified. These pathways include effects on neurotransmitter function, neuroendocrine activity, neural plasticity and alterations of brain circuitry (Fig. 3).

Sources of chronic inflammation

Chronic or non-resolving inflammation may originate from either pathophysiological (e.g., inflammatory diseases, immune-based disorders, T cell dysfunction) or non-pathological conditions including aging and obesity.

Translational implications

Given the vast knowledge base that has been elaborated regarding the capacity of inflammatory cytokines to influence behavior as well as the data detailing the potential mechanisms involved, there is a wide array of potential pharmacological and behavioral targets that may be relevant for the development of new treatments or prevention strategies for neuropsychiatric disorders including depression.

Conclusions

Brain–immune system interactions have opened up new vistas regarding the treatment and prevention of behavioral disorders. Given the interest in inflammation as a common mechanism of multiple diseases including cardiovascular disease, diabetes and cancer, the role of inflammation in neuropsychiatric diseases such as depression puts the neurosciences and psychiatry in lock step with other medical disciplines in identifying and targeting immune relevant molecules and pathways for the treatment of

References (197)

  • L. Capuron et al.

    Neurobehavioral effects of interferon-alpha in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions

    Neuropsychopharmacology

    (2002)
  • L. Capuron et al.

    Cytokines and psychopathology: lessons from interferon-alpha

    Biol Psychiatry

    (2004)
  • L. Capuron et al.

    Psychoneuroimmunology of depressive disorder: mechanisms and clinical implications

  • L. Capuron et al.

    Interferon-alpha-induced changes in tryptophan metabolism. relationship to depression and paroxetine treatment

    Biol Psychiatry

    (2003)
  • L. Capuron et al.

    Anterior cingulate activation and error processing during interferon-alpha treatment

    Biol Psychiatry

    (2005)
  • L. Capuron et al.

    Baseline mood and psychosocial characteristics of patients developing depressive symptoms during interleukin-2 and/or interferon-alpha cancer therapy

    Brain Behav Immun

    (2004)
  • L. Capuron et al.

    Depressive symptoms and metabolic syndrome: is inflammation the underlying link?

    Biol Psychiatry

    (2008)
  • J. Chen et al.

    Neuroinflammation and disruption in working memory in aged mice after acute stimulation of the peripheral innate immune system

    Brain Behav Immun

    (2008)
  • R. Dantzer

    Cytokine-induced sickness behavior: where do we stand?

    Brain Behav Immun

    (2001)
  • F.S. Dhabhar et al.

    Low serum IL-10 concentrations and loss of regulatory association between IL-6 and IL-10 in adults with major depression

    J Psychiatr Res

    (2009)
  • Y. Dowlati et al.

    A meta-analysis of cytokines in major depression

    Biol Psychiatry

    (2010)
  • R.S. Duman et al.

    A neurotrophic model for stress-related mood disorders

    Biol Psychiatry

    (2006)
  • N.I. Eisenberger et al.

    Why rejection hurts: a common neural alarm system for physical and social pain

    Trends Cogn Sci

    (2004)
  • D.L. Evans et al.

    Mood disorders in the medically ill: scientific review and recommendations

    Biol Psychiatry

    (2005)
  • R.A. Floyd

    Neuroinflammatory processes are important in neurodegenerative diseases: an hypothesis to explain the increased formation of reactive oxygen and nitrogen species as major factors involved in neurodegenerative disease development

    Free Radic Biol Med

    (1999)
  • C. Franceschi et al.

    Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans

    Mech Ageing Dev

    (2007)
  • F. Frenois et al.

    Lipopolysaccharide induces delayed FosB/DeltaFosB immunostaining within the mouse extended amygdala, hippocampus and hypothalamus, that parallel the expression of depressive-like behavior

    Psychoneuroendocrinology

    (2007)
  • J.P. Godbout et al.

    Age and neuroinflammation: a lifetime of psychoneuroimmune consequences

    Immunol Allergy Clin North Am

    (2009)
  • H.S. Haas et al.

    Neuroimmunomodulation via limbic structures—the neuroanatomy of psychoimmunology

    Prog Neurobiol

    (1997)
  • M. Hamidi et al.

    Glial reduction in amygdala in major depressive disorder is due to oligodendrocytes

    Biol Psychiatry

    (2004)
  • N.A. Harrison et al.

    Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity

    Biol Psychiatry

    (2009)
  • N.A. Harrison et al.

    Neural origins of human sickness in interoceptive responses to inflammation

    Biol Psychiatry

    (2009)
  • B.L. Hart

    Biological basis of the behavior of sick animals

    Neurosci Biobehav Rev

    (1988)
  • C.J. Henry et al.

    Peripheral lipopolysaccharide (LPS) challenge promotes microglial hyperactivity in aged mice that is associated with exaggerated induction of both pro-inflammatory IL-1beta and anti-inflammatory IL-10 cytokines

    Brain Behav Immun

    (2009)
  • H. Himmerich et al.

    Regulatory T cells increased while IL-1beta decreased during antidepressant therapy

    J Psychiatr Res

    (2010)
  • T. Ida et al.

    Cytokine-induced enhancement of calcium-dependent glutamate release from astrocytes mediated by nitric oxide

    Neurosci Lett

    (2008)
  • M.R. Irwin

    Human psychoneuroimmunology: 20 years of discovery

    Brain Behav Immun

    (2008)
  • M.R. Irwin et al.

    Impaired natural killer cell activity among depressed patients

    Psychiatry Res

    (1987)
  • M.R. Irwin et al.

    Depressive disorders and immunity: 20 years of progress and discovery

    Brain Behav Immun

    (2007)
  • S. Kent et al.

    Sickness behavior as a new target for drug development

    Trends Pharmacol Sci

    (1992)
  • E.V. Acosta-Rodriguez et al.

    Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells

    Nat Immunol

    (2007)
  • H. Akiyama et al.

    Cell mediators of inflammation in the Alzheimer disease brain

    Alzheimer Dis Assoc Disord

    (2000)
  • G.E. Alexander et al.

    Basal ganglia-thalamocortical circuits: parallel substrates for motor, oculomotor, “prefrontal” and “limbic” functions

    Prog Brain Res

    (1990)
  • H. Anisman et al.

    Cytokines as a precipitant of depressive illness: animal and human studies

    Curr Pharm Des

    (2005)
  • H. Anisman et al.

    Endocrine and cytokine correlates of major depression and dysthymia with typical or atypical features

    Mol Psychiatry

    (1999)
  • F. Annunziato et al.

    Phenotypic and functional features of human Th17 cells

    J Exp Med

    (2007)
  • J.P. Bastard et al.

    Elevated levels of interleukin 6 are reduced in serum and subcutaneous adipose tissue of obese women after weight loss

    J Clin Endocrinol Metab

    (2000)
  • J.P. Bastard et al.

    Evidence for a link between adipose tissue interleukin-6 content and serum C-reactive protein concentrations in obese subjects

    Circulation

    (1999)
  • O. Ben Menachem-Zidon et al.

    Intrahippocampal transplantation of transgenic neural precursor cells overexpressing interleukin-1 receptor antagonist blocks chronic isolation-induced impairment in memory and neurogenesis

    Neuropsychopharmacology

    (2008)
  • H.O. Besedovsky et al.

    Immune–neuro-endocrine interactions: facts and hypotheses

    Endocr Rev

    (1996)
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    Conflict of interest: The authors declare no conflict of interest.

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