Differential correlations between inflammatory cytokines and psychopathology in veterans with schizophrenia: Potential role for IL-17 pathway

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Abstract

Pro-inflammatory cytokines have been consistently reported to be elevated in schizophrenia patients. However, it is not known whether cytokines influence the presentation of psychotic symptoms. To address this issue, we evaluated the relationship between levels of inflammatory molecules and psychopathological parameters in patients with schizophrenia. We hypothesized that severity of symptoms would correlate with increased levels of inflammatory cytokines. Serum samples from 47 veterans with a diagnosis of schizophrenia and 20 healthy controls were tested for levels of 38 cytokines/chemokines involved in regulation of immune/inflammatory reactions using a Millipore multiplex bead array in a Luminex 100 system. We found significantly increased levels of GRO, MCP-1, MDC, and sCD40L, and significantly decreased levels of IFN-γ, IL-2, IL-12p70, and IL-17, in schizophrenia patients compared to controls. In addition, we observed positive correlations between levels of cytokines and the Positive and Negative Symptoms Scale (PANSS) scores in subjects with schizophrenia for G-CSF, IL-1β, IL1ra, IL-3, IL-6, IL-9, IL-10, sCD40L and TNF-β. Pathway analyses showed these cytokines to be part of the IL17 pathway. Using principal component analyses, we found the factor that included these cytokines and IL-17 to be associated with positive, general and total PANSS scores. These results suggest that alterations in this pathway may play a role in development of psychotic symptoms in schizophrenia.

Introduction

Alterations in the inflammatory system and conditions of enhanced innate immune response with overproduction and/or disbalance of pro-inflammatory cytokines have been associated with schizophrenia (Dimitrov et al., 2011). The importance of macrophages and T lymphocytes, and the cytokines produced by them, has been highlighted in the macrophage–T cell theory of bipolar disorder and schizophrenia (Smith, 1992, Drexhage et al., 2010). However, the mechanism by which immune system dysregulation may contribute to development of schizophrenia symptoms is not completely understood. When the integrity of the blood brain–barrier is intact, only a few mononuclear cells, activated T cells, and macrophages migrate into the CNS. However, pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α, released during peripheral inflammation, can signal through endothelial cells to cause alterations in the tight junction structure, leading to increased permeability of the blood–brain barrier and alterations in brain structure and function (Carter, 2009). Further, peripheral inflammation can cause an increased number of mononuclear cells permeating into the brain, leading to activation of the inflammatory cascade in the central nervous system (CNS) (Silverman et al., 2000). Comparison of cerebrospinal fluid samples of patients with schizophrenia to controls revealed that the proportion of mononuclear macrophages was significantly higher in individuals with schizophrenia (Nikkila et al., 1999). We also reported increased peripheral number of monocytes during episodes of worsening psychotic symptoms in veterans with schizophrenia (Dimitrov, 2011). In support of this are the findings that microglial cells, the macrophages of the brain, are activated during psychosis (Bessis et al., 2007). Cells visualized with a PET tracer (PK11195) which binds to peripheral benzodiazepine receptors, an indicator of microglia activation, were found to have greater receptor expression in patients with recent-onset schizophrenia (van Berkel et al., 2008). Activated microglia stimulate astrocytes to produce S100B, a marker of inflammation, that is considered to be the equivalent of C-reactive protein (CRP) in the brain (Sen and Belli, 2007). S100B serum levels are elevated in schizophrenia patients (Zhang et al., 2010) and antipsychotics such as haloperidol and clozapine have been shown to decrease S100B release from glial cells (Zhang et al., 2010). In addition to S100B, levels of many other inflammatory markers, primarily cytokines involved in Th1 and Th2 immune pathways, have been consistently found to be altered in schizophrenia patients, and this has been previously reviewed (Potvin et al., 2008, Monji et al., 2009, Watanabe et al., 2010, Miller et al., 2011). Based on these findings, the hypothesis of an imbalance between Th1 and Th2 cytokines in schizophrenia has been proposed (Müller et al., 1999). Further evidence of immune dysregulation in schizophrenia comes from studies where schizophrenia patients and their families have been reported to have greater incidence of autoimmune disorders, including type I diabetes, thyroid disorders and celiac disease, compared to controls (Benros et al., 2012). Indeed, a large linkage study of Danish National Registers reported a 45% greater risk of developing schizophrenia in families with a history of autoimmune disorders (Eaton et al., 2006). Furthermore, high levels of autoantibodies, including anticardiolipin, anti-histone, anti DNA and anti-nuclear antibodies have been reported in schizophrenia patients. Serum antibodies against brain specific regions such as the hippocampus, amygdala and frontal cortex have also been reported (Strous and Shoenfeld, 2006). Altogether, these studies are in accordance with the inflammatory hypotheses of schizophrenia and underline the importance of investigating the role of immune dysregulation in schizophrenia. By performing a comprehensive analysis of inflammatory markers in patients with schizophrenia from the Veterans Affairs (VA) system, we aimed to further examine the relationship between inflammatory cytokines and worsening of symptoms in schizophrenia. We hypothesized that patients with acute psychotic symptoms would exhibit activation of the inflammatory signaling cascade indicated by overproduction of pro-inflammatory cytokines. To the best of our knowledge such an approach for the study of patients with schizophrenia has not been performed in the VA system. These studies will improve our understanding of the etiology of schizophrenia and ultimately may lead to development of new treatments for schizophrenia.

Section snippets

Subjects

Forty seven veterans with a diagnosis of schizophrenia based on DSM-IV criteria were enrolled at the Mental Health Intensive Care Management (MHICM) clinic of the South Texas Veterans Health Care System (STVHCS). Twenty demographically matched healthy controls were recruited from the same community and screened with the SCID screening interview to rule out history of mental illness and family history of psychotic disorders. Subjects were excluded if they had prior history of significant

Demographic characteristics

Blood samples for this study were collected from a cohort of 47 patients undergoing treatment for schizophrenia (70%) and 20 healthy controls (30%). The ethnicity of the population was 49% Hispanic, 35% Caucasian, 13% African–American, and 3% Asian. The age range was between 29 and 62 years, with a patient average age of 54.5 ± 7.7 years and control average age of 41 ± 11.6 years. The gender distribution was 84% male and 16% female (Table 1). No significant differences in gender, ethnicity, BMI, or

Discussion

This study, although based on a relatively low sample size, is one of the first attempts to perform a comprehensive correlation between inflammatory markers and psychopathological scores obtained by PANSS. We found significant association between levels of cytokines and PANSS scores for G-CSF, IL-1β, IL-1ra, IL-3, IL-6, IL-9, IL-10, sCD40L and TNF-β (Fig. 1). To our knowledge, only one previous study described a significant inverse relationship between IL-2 and PANSS positive subscale (Zhang et

Role of funding source

The study was approved by the University of Texas Health Science Center at San Antonio and Veterans Affairs Research and Development Service and carried out in accordance with the Declaration of Helsinki. All participants provided written informed consent. All tests and reagents were provided by the VA and UTHSCSA.

Contributors

D.H. Dimitrov, S. Lee, J. Yantis, C. Valdez, R.M. Paredes, N. Braida, Dawn Velligan, C. Walss-Bass contributed to this article.

Conflict of interest

None of the authors have conflict of interest.

Acknowledgments

We thank Laurel A Copeland, PhD, Investigator, Central Texas Veterans Health Care System, for assistance with study design.

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