Neuropsychopharmacology REVIEWS (2017) 42, 1–4

EDITORIAL © 2017 American College of Neuropsychopharmacology All rights reserved 0893-133X/17

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The Immunology of Behavior—Exploring the Role of

the Immune System in Brain Health and Illness
Neuropsychopharmacology Reviews (2017) 42, 1–4; doi:10.1038/npp.2016.229

INTRODUCTION EVOLUTIONARY LEGACIES AND IMMUNE

Advances in our understanding of immunology especially
REGULATION OF BRAIN FUNCTION
cellular immunology and cytokine biology have led to In the first review, we are introduced to the concept that the
monumental changes in the practice of medicine. Indeed, immune system and the brain are intimately intertwined by
elucidation of the pathways involved in T-cell regulation virtue of an evolutionary past that included a marked selection
have led to a series of therapeutic agents referred to as pressure for synergy between immune and behavioral responses
‘checkpoint inhibitors’ that are revolutionizing the treatment to microbial challenges that jeopardized reproductive success.
of cancer. Similarly, the development of biological therapies These brain–immune interactions and their association with
that target cytokines and other mediators of the inflamma- aggressive innate immune responses and related behaviors of
tory response have changed the landscape of the treatment of avoidance and alarm, whereas essential for dealing with the
autoimmune and inflammatory disorders. These develop- threats of infection and wounding in ancestral times, are poorly
ments have impacted millions of lives and represent some of designed for dealing with threats from the social environments
the most important achievements of modern medicine. Not that humans confront in the modern world. Raison and Miller,
surprisingly, the revolution in immunology has made its way (2017) further examine the legacy of this evolutionary past in
to the basic and clinical neurosciences with a growing attempts to address fundamental questions regarding the role of
appreciation of the role of the immune system in brain the interconnectedness of the brain and immune system in
health and illness. From its participation in brain develop- understanding the genetics, bioregional differences, and female
ment to its contributions to adulthood disorders and preponderance in certain mental illnesses, notably mood
neurodegeneration, the immune system as a major regulator disorders. Further supporting evolutionary notions of synergis-
of neuronal function throughout the life cycle has attracted tic interactions between the brain and immune system is the
significant attention, enough so to warrant its own special increasing elaboration of the network of communication of the
issue of Neuropsychopharmacology reviews. In this issue, we peripheral immune system and the brain. Indeed, the long-held
have attempted to give a sample of the important research view that the brain is isolated from the peripheral immune
being conducted in this area with an emphasis on (1) the system due to the lack of circulating immune cells infiltrating
fundamental mechanisms by which the immune system the brain during homeostatic conditions is rapidly changing. In
supports neuronal integrity, (2) the pathways by which the the review by Marin and Kipnis, (2017), multiple layers of
peripheral and central immune compartments become immune surveillance of the central nervous system (CNS) are
activated and communicate—especially in the context of described, including an immune presence in the brain
(microglia) and compartmentalization of a full complement
stress, (3) the factors that represent risk and resilience for
of immune cells in the meninges and choroid plexus, the
both immune dysregulation and behavioral change, (4) the
responses of which can be communicated to the brain
impact of the immune system on neurotransmitter systems
parenchyma. The CNS benefits of this extensive support from
and neurocircuits that regulate behavior, and (5) the
immune surveillance during homeostasis is elaborated, as is a
immunological contributions to developmental disorders
role for these processes in protection of the CNS from the
and neurodegeneration. It should be noted, however, that
destructive effects of inflammation. These results highlight the
throughout the issue it is emphasized that no mental
essential collaboration of the immune system and the brain,
disorder is fundamentally an immunological disorder, rather
and its relevance for brain health and illness.
the point is repeatedly made that the immune system
potentially participates in a subgroup of symptoms that cut
across multiple psychiatric diseases. The therapeutic promise
STRESS-INDUCED IMMUNE ACTIVATION
of targeting different facets of the immune system is also
addressed in every review, and each review outlines the many
AND COMMUNICATION WITH THE BRAIN
gaps in our knowledge and what steps need to be taken to Given the well-known impact of stress on psychiatric disease,
move the field forward. there is a rich basic science literature using a variety of
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animal models to understand the immunological phospholipase A2, are associated with increased risk for
mechanisms by which stress contributes to the development depression. Moreover, these authors found that protein and
of neuropsychiatric disorders, especially mood and anxiety mRNA levels of inflammatory markers can predict the
disorders. In their review, Fleshner et al. (2017) discuss the response to conventional antidepressants. In addition to
importance of sterile (pathogen-free) activation of inflam- genetic vulnerability, childhood maltreatment can also affect
matory processes in both the periphery and CNS through the immune response, predisposing individuals to heigh-
stress-induced release of danger-associated molecular tened inflammatory states later in life that have long-term
patterns that stimulate the inflammasome, a molecular consequences on the brain and behavior. Danese and Lewis,
complex that leads to the release of inflammatory (2017) propose that these early-life stress effects on the
cytokines. They argue that the inflammasome serves as an immune response offer an innovative framework to under-
important point of integration in translating stress signals standing psychopathology linked to childhood trauma, and
into inflammation. Preclinical and clinical evidence is that remediating the effect of trauma on inflammation before
described regarding the role of sterile inflammation and the onset of clinical symptoms represents a novel prevention
inflammasome-dependent signaling in behavioral changes, strategy.
and the inflammasome is presented as an intriguing novel Metabolic disorders and obesity are also highly associated
target for blocking inflammation in the treatment of with psychiatric illnesses, such as depression, and may
neuropsychiatric disorders. Weber et al, (2017) elaborate involve adiposity-related, chronic low-grade inflammatory
on how stress can also disrupt homeostatic or ‘healthy’ processes that affect brain function and behavior. Capuron
bi-directional immune cell communication between the et al. (2017) review converging clinical and preclinical
peripheral immune system and CNS. They present elegant evidence for a bi-directional relationship between
data demonstrating that stress-induced increases in sympa- depression and adiposity, the immunological and metabolic
thetic nervous system outflow can bias hematopoietic stem mechanisms of which may provide identification of
cells to differentiate into glucocorticoid-resistant, primed preventive and/or therapeutic strategies. Sleep disturbances
myeloid lineage cells that can then be recruited to the brain including insomnia are another risk factor that may
by microglia and endothelial cells. Once in the brain, these
independently contribute to inflammatory disorders and
cells can reinforce and maintain stress-related behavioral
other medical illnesses as well as neuropsychiatric disorders
pathology (Weber et al, 2017). Menard et al. (2017
including depression. Irwin and Opp, (2017) provide an
discuss the nuances of the immunological response to stress
integrated understanding of reciprocal relationships between
by detailing the cellular and molecular mechanisms of risk
sleep and the innate immune response, including the effects
and resilience that shape stress-induced behavioral
of inflammatory mediators on homeostatic regulation of
vulnerabilities. Special attention is paid to individual and
sleep continuity and macrostructure and the potential for
sex-specific differences in immunological and neuroendo-
interventions that target insomnia and other sleep
crine responses that drive peripheral and central immune cell
disturbances to reverse inflammation. In a review addressing
activation (Menard et al, 2017). Specifically, they discuss
cytokine signaling, peripheral monocyte infiltration, the role of the immune system in substance abuse,
microglial activation, and hypothalamic-pituitary-adrenal Lacagnina et al. (2017) describe mechanisms by which
axis hyperactivity in stress vulnerability and coping, microglia and astrocytes perform critical functions in
while highlighting the potential for adaptive immune synapse formation, refinement, and remodeling, and how
responses and immune modulators to decrease depressive these processes are modified by drugs of abuse to
symptoms. contribute to the liability to addictive disorders. Indeed,
drugs of abuse can activate microglia through signaling at
innate immune receptors (toll-like receptors), in turn
influencing neuronal function and synapse integrity which
GENETIC AND OTHER MEDIATORS OF RISK predisposes to later vulnerability to substance abuse. Finally,
FOR IMMUNE DYSREGULATION AND there is increasing appreciation that the microbiome and its
PSYCHIATRIC DISEASE regulation of the immune response may also have a role in
Complementing animal models of risk and resilience to the risk and resilience for neuropsychiatric disease. Indeed,
stress-induced, immune-based behavioral changes, the growth of ‘friendly’ probiotic microbes in the
numerous studies have demonstrated genetic and other risk gut creates a positive host immune environment, while
factors for increased inflammation and changes in immune dampening the effects of chronic, non-resolving inflamma-
function that are believed to contribute to both the tory responses. In their far-reaching review, Dinan and
development and treatment responsiveness of neuropsychia- Cryan, (2017) propose that depletion of ‘friendly’ commensal
tric disorders. For example, in a systematic review of the populations in the gut contributes to the harmful effects of
literature, Barnes et al. (2017) report that common genetic stress and inflammation, and can be replenished by the
variants, including polymorphisms in genes for interleukin use of prebiotics, probiotics, and/or fecal microbiota
(IL)-1beta, IL-6, IL-10, monocyte chemoattractant transplantation to benefit patients with psychiatric and
protein-1, tumor necrosis factor, C-reactive protein, and medical illnesses.
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IMPACT OF THE IMMUNE SYSTEM ON suicidal behavior seen across psychiatric disorders.
NEUROTRANSMITTERS, NEUROCIRCUITS On the basis of this association, they propose that
AND BEHAVIOR biomarkers of inflammation and its downstream mediators
including metabolites of the kynurenine pathway, which
Activation of the innate immune response and release of relate to both serotonin and glutamate, may provide not only
inflammatory cytokines can influence monoaminergic and a mechanism by which suicidal behavior occurs, but also a
glutamatergic pathways that regulate motivation and motor biological estimate of suicide risk. Taken together, these
activity as well as threat sensitivity, to contribute to findings suggest that the immune system can affect
behavioral symptoms that cut across a number of psychiatric fundamental pathways that regulate behavior and thereby
disorders. For example, a wealth of clinical and preclinical represents a critical pathway to pathology in neuropsychia-
data suggest mechanisms by which inflammation can impact tric diseases.
glutamate, including failed clearance and exaggerated release
of glutamate by glial cells, aberrant extrasynaptic signaling
through ionotropic and metabotropic glutamate receptors,
and loss of synaptic fidelity via glutamate diffusion outside of IMMUNE CONTRIBUTIONS TO
the synapse. As proposed by Haroon et al. (2017), these DEVELOPMENTAL DISORDERS AND
changes in glutamate during innate immune activation may NEURODEGENERATION
ultimately result in synaptic and circuit dysfunction that is As indicated above, many of the details regarding the basic
relevant to behavioral pathology and its treatment in mood and clinical mechanisms by which the immune system can
disorders. Numerous laboratories have also found that affect the brain have been elaborated. Therefore, the
peripheral inflammatory stimuli can affect reward and other opportunity exists to apply this knowledge to the role of
basal ganglia circuits to contribute to motivational and motor the immune system in the development and neuroprogres-
deficits that are common in patients with depression and sion of a variety of mental disorders. Much of the attention
other psychiatric disorders. Felger and Treadway, (2017) of the impact of the immune system on psychiatric disease
highlight recent clinical and translational data regarding the has occurred within the context of mood disorders. However,
role of inflammation effects on dopamine in these alterations there is a growing literature regarding a number of other
in corticostriatal circuit function, reduced motivation, and metal illnesses. Both schizophrenia and autism spectrum
motor slowing, in relation to novel therapeutic strategies to disorders are diseases with an important developmental
treat these symptoms in patients with high inflammation. In component, and data suggest that shared genetic risk
terms of inflammation effects on threat-relevant circuitry, interacting with prenatal immune activation resulting from
Eisenberger et al. (2017) discuss evidence of and implications maternal infection may be involved in both disorders.
for the co-regulation of inflammation and social behavior via Variations in the clinical and phenotypic presentation might
neural circuitry that promotes adaptation to social environ- be attributed to distinct contributions from maternal and
ments during times of stress or sickness. Specifically, acute fetal immune responses. For example, as suggested by
inflammation increases threat-related neural sensitivity to Meltzer and Van de Water, (2017), autism spectrum
negative social experiences, presumably to promote avoiding disorders may result from maternal and/or host autoanti-
challenge to well-being or safety, while increasing reward- bodies that selectively disrupt neural circuits regulating social
related neural sensitivity and approach motivation toward behavior. On the other hand, as discussed by Miller and
positive social experiences that might provide support or Goldsmith, (2017), schizophrenia might represent excessive
care during sickness. Conversely, social behavior may also pruning of large-scale networks by over-active innate and
regulate aspects of inflammatory activity, preparing the body adaptive immune responses leading to neurotransmitter
for situations in which wounding and infection are more dysregulation. On the basis of these hypotheses, common
likely. Related to these considerations, Michopoulos et al, treatment/prevention for both disorders might include some
(2017) describe a growing interest in the role of inflamma- overlapping components of screening/testing for prenatal
tion and immune activation in fear and/or anxiety disorders, infections and autoantibodies and preventative immunomo-
including posttraumatic stress disorder, generalized anxiety dulatory therapies in at-risk populations. Divergent
disorder, panic disorder, and phobias. Exposure to stress or approaches might include treatments targeting autoimmu-
trauma and associated dysregulation of the neuroendocrine nity in autism spectrum disorders vs a broader, anti-
and autonomic systems that characterize these disorders may inflammatory, and neuroprotective strategy in schizophre-
precipitate inflammatory states and the release of cytokines nia, which reflects the potential impact of the immune
that then contribute to increased symptom severity via system on both developmental and degenerative processes in
effects on brain circuits critical for the regulation of fear and the disorder. Of note, consistent with the impact of
anxiety (eg, prefrontal cortex, insula, amygdale, and inflammation on neurocircuits involved in reward, special
hippocampus). These effects of inflammation on neuro- consideration is given to the role of inflammation in negative
transmitters and neurocircuits are further extended in the symptoms as well as cognition in schizophrenia. Finally, the
review by Brundin et al. (2017) who report a consistent effects of stress-induced immune activation on aging
association between increased inflammatory activation and immune cells (including microglia) is reviewed by Niraula
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et al, (2017) who describe age-related generation of a hyper- Danese A, Lewis S (2017). Psychoneuroimmunology of early life stress: the hidden
responsive and pro-inflammatory ‘primed’ phenotype that wounds of childhood trauma? Neuropsychopharmacology 42: 99–114.
Dinan TG, Cryan JF (2017). Microbes, immunity, and behavior: psychoneuroimmu-
has been consistently associated with neurodegeneration and nology meets the microbiome. Neuropsychopharmacology 42: 178–192.
accelerated aging. Eisenberger NI, Moieni M, Inagaki TK, Muscatell KA, Irwin MR (2017). In
sickness and in health: the co-regulation of inflammation and social behavior.
Neuropsychopharmacology 42: 242–253.
Felger JC, Treadway MT (2017). Inflammation effects on motivation and motor
TRANSLATIONAL IMPLICATIONS activity: role of dopamine. Neuropsychopharmacology 42: 216–241.
Fleshner M, Frank M, Maier SF (2017). Danger signals and inflammasomes:
In the final review of this series, the editors of this issue stress-evoked sterile inflammation in mood disorders. Neuro-
address the question of whether the extant literature has psychopharmacology 42: 36–45.
Haroon E, Miller AH, Sanacora G (2017). Inflammation, glutamate and glia: a trio of
reached the tipping point whereby immune-based therapies trouble in mood disorders. Neuropsychopharmacology 42: 193–215.
are ready for prime time (Miller et al, 2017). The general Irwin MR, Opp MR (2017). Sleep health: reciprocal regulation of sleep and innate
consensus is that the time has come for the rubber to meet immunity. Neuropsychopharmacology 42: 129–155.
Lacagnina MJ, Rivera PD, Bilbo SD (2017). Glial and neuroimmune mechanisms
the road, and a series of guidelines are set forth for intelligent as critical modulators of drug use and abuse. Neuropsychopharmacology 42:
clinical trial design. In addition, a series of relevant targets 156–177.
and treatments are described. The reader is left with a sense Marin IA, Kipnis J (2017). Central nervous system: (immunological) ivory tower
or not? Neuropsychopharmacology 42: 28–35.
of excitement regarding the future success of immune-based Meltzer A, Van de Water J (2017). The role of the immune system in autism spectrum
therapies titrated by the burden of proof. Indeed, the disorder. Neuropsychopharmacology 42: 284–298.
question remains unanswered whether the clinical neuros- Menard C, Pfau ML, Hodes GE, Russo SJ (2017). Immune and
neuroendocrine mechanisms of stress vulnerability and resilience. Neuropsycho-
ciences will benefit from the revolution in immunology as pharmacology 42: 62–80.
have so many other fields of medicine. The editors of this Michopoulos V, Powers A, Gillespie CF, Ressler KJ, Jovanovic T (2017).
issue believe the answer to this question is resoundingly yes. Inflammation in fear- and anxiety-based disorders: PTSD, GAD, and beyond.
Neuropsychopharmacology 42: 254–270.
Miller AH, Haroon E, Felger JC (2017). Therapeutic implications of brain-immune
FUNDING AND DISCLOSURE interactions: treatment in translation. Neuropsychopharmacology 42: 334–359.
Miller BJ, Goldsmith DR (2017). Towards an immunophenotype of
schizophrenia: progress, potential mechanisms, and future directions. Neurop-
All authors declare no conflict of interest. AHM and EH have sychopharmacology 42: 299–317.
no financial disclosures. In the past 3 years, JCF has Niraula A, Sheridan JF, Godbout JP (2017). Microglia priming with aging and stress.
consulted for Proctor and Gamble and Pfizer. No funding Neuropsychopharmacology 42: 318–333.
Raison CL, Miller AH (2017). Pathogen-host defense in the evolution of depression:
or sponsorship was provided by these companies for the insights into epidemiology, genetics, bioregional differences and female pre-
current work, and all views expressed herein are solely those ponderance. Neuropsychopharmacology 42: 5–27.
of authors. Weber MD, Godbout JP, Sheridan JF (2017). Repeated social defeat,
neuroinflammation, and behavior: monocytes carry the signal.
Neuropsychopharmacology 42: 46–61.
REFERENCES
Barnes J, Mondelli V, Pariante CM (2017). genetic contributions of inflammation to
Andrew H Miller1, Ebrahim Haroon1 and
depression. Neuropsychopharmacology 42: 81–98. Jennifer C Felger1
Brundin L, Bryleva EY, Thirtamara Rajamani K (2017). Role of inflammation in suicide: 1
Department of Psychiatry and Behavioral Sciences, Emory
from mechanisms to treatment. Neuropsychopharmacology 42: 271–283.
Capuron L, Lasselin J, Castanon N (2017). Role of adiposity-driven inflammation in University School of Medicine, Atlanta, GA, USA
depressive morbidity. Neuropsychopharmacology 42: 115–128. E-mail: [email protected]

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