ABSTRACT
Positron emission tomography (PET) with translocator 18â¯kDa protein (TSPO) radioligands has frequently been used to investigate microglial activation in schizophrenia in vivo. However, the specificity of this marker is increasingly debated. Here we show that TSPO expression is 1) not increased in postmortem brain tissue of schizophrenia patients; 2) not correlated with expression of microglial activation markers; 3) not restricted to microglia; and 4) not upregulated in ex vivo activated human primary microglia. Our data are in line with recent reports showing that TSPO expression is not increased in schizophrenia and that it is not a specific marker for activated microglia. This study emphasizes the need for further development of tracers to study the role of microglial activation in schizophrenia and other diseases.
Subject(s)
Brain/metabolism , Inflammation/metabolism , Microglia/metabolism , Schizophrenia/metabolism , Aged , Aged, 80 and over , Autopsy , Biomarkers/metabolism , Female , Humans , Inflammation/immunology , Male , Middle Aged , Positron-Emission Tomography , Receptors, GABA , Schizophrenia/immunology , Tissue BanksABSTRACT
The biology of microglia has become subject to intense study, as they are widely recognized as crucial determinants of normal and pathologic brain functioning. While they are well studied in animal models, it is still strongly debated what specifies most accurately the phenotype and functioning of microglia in the human brain. In this study, we therefore isolated microglia from postmortem human brain tissue of corpus callosum (CC) and frontal cortex (CTX). The cells were phenotyped for a panel of typical microglia markers and genes involved in myeloid cell biology. Furthermore, their response to pro- and anti-inflammatory stimuli was assessed. The microglia were compared to key human myeloid cell subsets, including monocytes, monocyte-derived macrophages and monocyte-derived dendritic cells, and several commonly used microglial cell models. Protein and mRNA expression profiles partly differed between microglia isolated from CC and frontal cortex and were clearly distinct from other myeloid subsets. Microglia responded to both pro- (LPS or poly I:C) and anti-inflammatory (IL-4 or dexamethasone) stimuli. Interestingly, pro-inflammatory responses differed between microglia and monocyte-derived macrophages, as the former responded more strongly to poly I:C and the latter more strongly to LPS. Furthermore, we defined a large phenotypic discrepancy between primary human microglia and currently used microglial cell models and cell lines. In conclusion, we further delineated the unique and specific features that discriminate human microglia from other myeloid subsets, and we show that currently used cellular models only partly reflect the phenotype of primary human microglia. GLIA 2016;64:1857-1868.
