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Is there a role for immune-to-brain communication in schizophrenia?

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Abstract

Schizophrenia is characterised by hallucinations, delusions, depression-like so-called negative symptoms, cognitive dysfunction, impaired neurodevelopment and neurodegeneration. Epidemiological and genetic studies strongly indicate a role of inflammation and immunity in the pathogenesis of symptoms of schizophrenia. Evidence accrued over the last two decades has demonstrated that there are a number of pathways through which systemic inflammation can exert profound influence on the brain leading to changes in mood, cognition and behaviour. The peripheral immune system-to-brain communication pathways have been studied extensively in the context of depression where inflammatory cytokines are thought to play a key role. In this review, we highlight novel evidence suggesting an important role of peripheral immune-to-brain communication pathways in schizophrenia. We discuss recent population-based longitudinal studies that report an association between elevated levels of circulating inflammatory cytokines and subsequent risk of psychosis. We discuss emerging evidence indicating potentially important role of blood–brain barrier endothelial cells in peripheral immune-to-brain communication, which may be also relevant for schizophrenia. Drawing on clinical and preclinical studies, we discuss whether immune-mediated mechanisms could help to explain some of the clinical and pathophysiological features of schizophrenia. We discuss implication of these findings for approaches to diagnosis, treatment and research in future. Finally, pointing towards links with early-life adversity, we consider whether persistent low-grade activation of the innate immune response, as a result of impaired foetal or childhood development, could be a common mechanism underlying the high comorbidity between certain neuropsychiatric and physical illnesses, such as schizophrenia, depression, heart disease and type-two diabetes.

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Abbreviations

BBB:

Blood–brain barrier

HSV-2:

Herpes simplex virus type-2

HSV-1:

Herpes simplex virus type-1

CRP:

C-reactive protein

TNF-α:

Tumour necrosis factor alpha

IL-8:

Interleukin 8

CNS:

Central nervous system

NMDAR:

N-methyl-d-aspartate receptor

GWAS:

Genome-wide association studies

MHC:

Major histocompatibility complex

ALSPAC:

Avon longitudinal study of parents and children

PAMPs:

Pathogen-associated molecular patterns

CVOs:

Circumventricular organs

DSM-IV:

Diagnostic and Statistical Manual Fourth Revision

ICD-10:

International Classification of Disease Tenth Revision

STAT:

Signal transducer and activator of transcription

CSF:

Cerebrospinal fluid

NDST3:

Bifunctional heparan sulphate N-deacetylase/N-sulfotransferase 3

COX:

Cyclooxygenase

11β-HSD2:

11beta-hydroxysteroid dehydrogenase type 2

HPA:

Hypothalamic-pituitary-adrenal

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Acknowledgements

The authors thank Prof Andrew Miller, Emory University, for supplying a high-resolution image for Fig. 3 from his publication. GK was supported by a clinical research fellowship grant from the Wellcome Trust (094790/Z/10/Z; 2010–13). RD received grants from the National Institute of Neurological Diseases and Stroke of the National Institutes of Health (grants R01 NS073939; R01 NS074999).

Conflict of interest

GK has no conflicts of interest to disclose. RD has received consulting fee and honorarium from Ironwood Pharma (USA) and Pfizer (France).

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  1. Department of Psychiatry, University of Cambridge, Box 189, Cambridge Biomedical Campus, Cambridge, CB2 2QQ, UK

    Golam M. Khandaker

  2. Department of Symptom Research, Division of Internal Medicine, MD Anderson Cancer Center, Houston, TX, USA

    Robert Dantzer

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Khandaker, G.M., Dantzer, R. Is there a role for immune-to-brain communication in schizophrenia?. Psychopharmacology 233, 1559–1573 (2016). https://doi.org/10.1007/s00213-015-3975-1

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