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

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.

Keywords: Blood–brain barrier; CRP; Common-cause hypothesis; Cytokine; Endothelial cell; IL-6; Immune system; Immunity; Inflammation; Psychotic disorder; Schizophrenia; Treatment.

Fig. 1

Associations between serum IL-6 levels at age 9 years, and psychotic disorder, psychotic symptoms and depression at age 18 years in the ALSPAC cohort. Samples of psychotic disorder (a), psychotic symptoms (b) and depression (c) at age 18 years were divided by tertiles of interleukin 6 (IL-6) at age 9 years. Cut-off values for the top and bottom thirds of the distribution of IL-6 values in the total sample (cases and non-cases combined) were 1.08 and 0.57 pg/mL, respectively. Adapted with permission (Khandaker et al. 2014a)

Fig. 2

Peripheral immune system-to-brain communication pathways. CVO=circumventricular organ, PGE2=prostaglandins, NO=nitric oxide, NTS=nucleus tractus solitaries, MCP-1=monocyte chemoattractant protein-1, IL-6=interleukin-6, IL-1β=interleukin-1β, TNFα=tumor-necrosis factor alpha. Reprinted with permission (Capuron and Miller 2011)

Fig. 3

IDO and the kynurenine pathway in inflammation-induced CNS pathology. Cytokine-induced activation of IDO in peripheral immune cells (e.g. macrophages and dendritic cells) or cells in the brain (e.g. microglia, astrocytes, and neurons) leads to the production of kynurenine, which is converted to kynurenic acid (KA) by the enzyme KAT-II in astrocytes, or quinolinic acid by the enzymes kynurenine-3-monooxygenase (KMO) and 3-hydroxy-anthranilic acid oxygenase (3 HAO) in microglia or infiltrating macrophages. Through blockade of the alpha 7 nicotinic acetylcholine receptor (a7nAChR), KA can contribute to cognitive dysfunction. Quinolinic acid can contribute to excitotoxicity, oxidative stress, and neurodegeneration. Reprinted by permission from Macmillan Publishers Ltd (Haroon et al. 2012)