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.

Childhood interleukin-6, C-reactive protein and atopic disorders as risk factors for hypomanic symptoms in young adulthood: a longitudinal birth cohort study

“…However, it is notable that serotonin-and tryptophan-degrading enzymes are activated by inflammatory cytokines such as IL-6 (Müller & Schwarz, 2007). As well as influencing monoamine cascades, cytokine production has effects on cholinergic, muscarinic and gutamatergic systems which are associated with a range of affective and psychotic symptoms (Berk et al 2011;Khandaker & Dantzer, 2016). The potential effects of IL-6 in particular are complex; it is implicated in activation of the immune system (as a proinflammatory cytokine), but it is also involved in the antiinflammatory regulation of neural, regenerative and metabolic activity (Scheller et al 2011).…”

“…The potential effects of IL-6 in particular are complex; it is implicated in activation of the immune system (as a proinflammatory cytokine), but it is also involved in the antiinflammatory regulation of neural, regenerative and metabolic activity (Scheller et al 2011). Peripheral cytokines such as IL-6 can communicate with the brain in a number of ways (Khandaker & Dantzer, 2016). Immunoactivation in mice and healthy volunteers by injection of lipopolysaccharide has been reported to increase circulating proinflammatory cytokine levels (IL-1β, IL-6) as well as producing symptoms of anxiety and reduced cognitive performance (Reichenberg et al 2001;Rossi et al 2012).…”

Altered serum levels of interleukin-3 in first-episode drug-naive and chronic medicated schizophrenia

“…Specific mediators of this linkage between schizophrenia and the immune system include cytokines, which are critical chemical messengers of the cross-talk between the central nervous system (CNS) and immune cells (Potvin et al, 2008;Khandaker and Dantzer, 2015). Many changes in cytokines and their receptors are essential in the regulation of normal brain development and have been associated with schizophrenia (Potvin et al, 2008;Miller et al, 2011) and with specific types of symptoms in schizophrenia (Kim et al, 2000;Zhang et al, 2002;Fan et al, 2007b).…”

Human dermal fibroblasts in psychiatry research

“…Peripheral leukocytes, and particularly peripheral blood derived mononuclear cells have a long history of use in psychiatric research, assuming a bidirectional communication between the immune and nervous systems (Khandaker and Dantzer, 2015; Naydenov et al, 2007). It has been argued that peripheral leukocytes and brain cells share considerable similarities in their proteome, signaling signature, and hormone and drug response (Gladkevich et al, 2004; Iga et al, 2008).…”