The role of inflammation in schizophrenia

Abstract

High levels of pro-inflammatory substances such as cytokines have been described in the blood and cerebrospinal fluid of schizophrenia patients. Animal models of schizophrenia show that under certain conditions an immune disturbance during early life, such as an infection-triggered immune activation, might trigger lifelong increased immune reactivity. A large epidemiological study clearly demonstrated that severe infections and autoimmune disorders are risk factors for schizophrenia. Genetic studies have shown a strong signal for schizophrenia on chromosome 6p22.1, in a region related to the human leucocyte antigen (HLA) system and other immune functions. Another line of evidence demonstrates that chronic (dis)stress is associated with immune activation. The vulnerability-stress-inflammation model of schizophrenia includes the contribution of stress on the basis of increased genetic vulnerability for the pathogenesis of schizophrenia, because stress may increase pro-inflammatory cytokines and even contribute to a lasting pro-inflammatory state. Immune alterations influence the dopaminergic, serotonergic, noradrenergic, and glutamatergic neurotransmission. The activated immune system in turn activates the enzyme indoleamine 2,3-dioxygenase (IDO) of the tryptophan/kynurenine metabolism which influences the serotonergic and glutamatergic neurotransmission via neuroactive metabolites such as kynurenic acid. The described loss of central nervous system volume and the activation of microglia, both of which have been clearly demonstrated in neuroimaging studies of schizophrenia patients, match the assumption of a (low level) inflammatory neurotoxic process. Further support for the inflammatory hypothesis comes from the therapeutic benefit of anti-inflammatory medication. Metaanalyses have shown an advantageous effect of cyclo-oxygenase-2 inhibitors in early stages of schizophrenia. Moreover, intrinsic anti-inflammatory, and immunomodulatory effects of antipsychotic drugs are known since a long time. Anti-inflammatory effects of antipsychotics, therapeutic effects of anti-inflammtory compounds, genetic, biochemical, and immunological findings point to a major role of inflammation in schizophrenia.

Leukocyte telomere length: Effects of schizophrenia, age, and gender

“…Other possible contributors to LTL shortening include inflammation, oxidative stress, and certain chronic viral infections (reviewed in: Lindqvist et al, 2015). These factors may be increased in schizophrenia compared to HCs (Emiliani et al, 2014;Muller et al, 2015;Shivakumar et al, 2014). This could, in theory, result in shortened LTL, but there is only mixed evidence that these factors are differentially prevalent in men vs women with schizophrenia (Joseph et al, 2015;Kunz et al, 2011;Lee et al, 2016;Ramsey et al, 2013;Reyazuddin et al, 2014).…”

Neuregulin-1 and schizophrenia in the genome-wide association study era

“…social behavior, spatial working memory, PPI) among TM Nrg1 mice exposed to maternal immune activation (O'Leary et al 2014). These clinical and preclinical findings are particularly relevant given evidence of an increase in pro-inflammatory cytokines in schizophrenia (Muller et al 2015) and is further supported by reports that NRG1 influences cell adhesion of immune cells (Kanakry et al 2007) and decreases the release of free radicals from microglial cells (Dimayuga et al 2003). Furthermore, a recent study (Sekar et al 2016) has highlighted complement 4 gene within the major histocompatibility complex (MHC) playing a leading role in synaptic dysregulation and risk for schizophrenia and therefore Nrg1 may act in concert with complement 4 and other genes in the MHC region to enhance risk for schizophrenia, perhaps via stimulation of proinflammatory markers that contribute to autoimmune activation of complement in the brain.…”

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

“…Abnormal activation of the immune system may play an important role in the pathogenesis of schizophrenia (Fan et al, 2007a;Müller et al, 2012Müller et al, , 2015Müller, 2013;Smyth and Lawrie, 2013;Altamura et al, 2014;Horvath and Mirnics, 2014;Tomasik et al, 2014;Sperner-Unterweger and Fuchs, 2015) based on genetic, animal model, clinical markers and treatment studies (Potvin et al, 2008;Miller et al, 2011Miller et al, , 2013Fineberg and Ellman, 2013). Genetic evidence includes a recent genome-wide association study (GWAS) that has indicated a close relationship between genes regulating immune response and many schizophrenia risk genes (Schizophrenia Working Group of the Psychiatric Genomics, 2014).…”