Characterization of macrophages from schizophrenia patients

Paul R Ormel,Lot D De Witte,Manja Litjens,Hans C Van Mierlo,Elly M Hol,René S Kahn,Miriam E Van Strien

doi:10.1038/s41537-017-0042-4

Abstract

Genetic, epidemiological and post mortem studies have described an association between schizophrenia (SCZ) and the immune system. Microglia, the tissue-resident macrophages of the brain, not only play an essential role in inflammatory processes, but also in neurodevelopment and synapse refinement. It has therefore been hypothesized that aberrant functioning of these myeloid immune cells is involved in SCZ pathogenesis. Until now cellular research into the role of myeloid cells in SCZ has been limited to monocytes and functional assays are lacking. In this study we used monocyte-derived macrophages (mo-MΦs) as a model for macrophages and microglia in the CNS and examined two main functions: Inflammatory responses and expression and regulation of synapse refinement molecules. The expression of 24 genes involved in these key functions was assessed. Mo-MΦs were generated from 15 SCZ patients and 15 healthy controls. The cells were exposed to pro-inflammatory and anti-inflammatory stimuli (LPS, R848, IL-4 and dexamethasone), and the response was measured by qPCR and ELISA analyses. One of the genes of interest, P2RX7 that is associated with psychiatric diseases, was significantly reduced in expression after LPS stimulation in SCZ patients. None of the other assessed characteristics were different in this functional screen between mo-MΦs from SCZ patients compared to controls. Although these data suggest that overall the function of macrophages in SCZ is not impaired, further studies with larger groups that enable the possibility to study clinical subgroups and perform additional screenings to asses the full phenotype of the mo-MΦs are needed to strengthen this conclusion.

Highlights

Schizophrenia (SCZ) is a psychiatric disorder that is caused by the interplay between genetic and environmental factors
Single-nucleotide polymorphisms in immune genes are associated with the disease,[2,3] the prevalence of immune-related disorders is higher in patients and their family members,[4] and altered levels of immunological markers are measured in blood, cerebrospinal fluid and brain tissue of SCZ patients compared to controls.[5,6,7]
Which immunological pathways are affected in SCZ is still elusive as well as how these pathways contribute to synaptic deficits underlying SCZ pathogenesis

Summary

INTRODUCTION

Schizophrenia (SCZ) is a psychiatric disorder that is caused by the interplay between genetic and environmental factors. Since it is not possible to obtain primary microglia and macrophages from the CNS from living individuals, we performed a functional screen of monocytes from SCZ patients and controls that were differentiated into macrophages in vitro. This model, inducing the so-called monocyte-derived macrophages (moMΦs), is widely used in immunological research for functional experiments on macrophages.[21] We screened the mo-MΦs for (1) The expression of genes involved in inflammation and the response to pro-inflammatory and anti-inflammatory molecules and (2) The expression and regulation of synapse refinementrelated receptors

RESULTS

DISCUSSION

10-2 UND: Gene

METHODS