Common and disorder-specific upregulation of the inflammatory markers TRAIL and CCL20 in depression and schizophrenia

Federica Klaus,Rebecca Schlegel,Flurin Cathomas,Tobias R Spiller,Stefan Kaiser,Erich Seifritz,Karoline Guetter

doi:10.1038/s41598-021-98769-0

Abstract

Schizophrenia (SZ) and major depressive disorder (MDD) are severe mental disorders, which have been associated with alterations of the peripheral inflammatory network. However, studies for both disorders have not been fully consistent and have focused on few canonical markers with high relevance to the innate immune system, while the role of the adaptive immune system is studied less. Furthermore, it is unclear to what extent inflammatory abnormalities are diagnosis-specific or transdiagnostic. The purpose of this study was to investigate 75 peripheral inflammatory markers including the acute phase protein high-sensitivity C-reactive protein (hsCRP) in patients with MDD (n = 37), SZ (n = 42) and healthy controls (HC) (n = 17), while considering possible confounders and correcting rigorously for multiple testing in group comparisons. We identified C–C chemokine ligand 20 (CCL20) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as the inflammatory markers with significant group differences after controlling for multiple comparisons and adjusting for BMI, sex and smoking as confounders. TRAIL was elevated in both MDD and SZ compared to HC. CCL20 was specifically increased in SZ compared to MDD and HC. There were no significant group differences in hsCRP after correcting for multiple testing. Finally, we observed no significant correlations among CCL20, TRAIL and CRP. TRAIL is a transdiagnostic marker for SZ and MDD, with both markers being independent from CRP and body mass index (BMI). CCL20 may be a novel and specific biomarker of schizophrenia, but an influence of antipsychotic medication cannot be excluded. Identifying novel markers in mental disease bears the potential for future research towards novel treatment strategies by modifying inflammation-related processes.

Highlights

Schizophrenia (SZ) and major depressive disorder (MDD) are severe mental disorders, which have been associated with alterations of the peripheral inflammatory network
We investigated differences in 75 peripheral inflammatory markers including the acute phase protein C-reactive protein (CRP) between patients with MDD, SZ and healthy controls (HC)
After correcting for body mass index (BMI), sex and smoking as covariates and correcting for multiple testing within the 74 inflammatory markers, significant differences emerged for C chemokine ligand 20 (CCL20) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)

Summary

Introduction

Schizophrenia (SZ) and major depressive disorder (MDD) are severe mental disorders, which have been associated with alterations of the peripheral inflammatory network Studies for both disorders have not been fully consistent and have focused on few canonical markers with high relevance to the innate immune system, while the role of the adaptive immune system is studied less. In MDD, the same meta-analysis revealed increased levels of IL-6 in chronically ill patients, and a decrease of IL-6, IL-10 and IL-12 levels following treatment of acute depression[25] Another consideration is that there is a bias in the literature towards a focus on a few canonical cytokines and chemokines with high relevance to the innate immune system, while the role of the adaptive immune system in mental health, schizophrenia and depression, is studied less[29,30,31]. There is evidence suggesting autoimmune components in SZ, altered lymphocyte count ratios, lymphocyte infiltration in brain regions relevant to psychosis and a recent paradigm of neuronal surface antibody-mediated central nervous system disease provides an antigen-specific model linking adaptive autoimmunity to p sychopathology[32]

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