Transmembrane protein 119 is neither a specific nor a reliable marker for microglia

Abstract

Microglia are the resident innate immune cells of the central nervous system (CNS) parenchyma. To determine the impact of microglia on disease development and progression in neurodegenerative and neuroinflammatory diseases, it is essential to distinguish microglia from peripheral macrophages/monocytes, which are eventually equally recruited. It has been suggested that transmembrane protein 119 (TMEM119) serves as a reliable microglia marker that discriminates resident microglia from blood‐derived macrophages in the human and murine brain. Here, we investigated the validity of TMEM119 as a microglia marker in four in vivo models (cuprizone intoxication, experimental autoimmune encephalomyelitis (EAE), permanent filament middle cerebral artery occlusion (fMCAo), and intracerebral 6‐hydroxydopamine (6‐OHDA) injections) as well as post mortem multiple sclerosis (MS) brain tissues. In all applied animal models and post mortem MS tissues, we found increased densities of ionized calcium‐binding adapter molecule 1+ (IBA1+) cells, paralleled by a significant decrease in TMEM119 expression. In addition, other cell types in peripheral tissues (i.e., follicular dendritic cells and brown adipose tissue) were also found to express TMEM119. In summary, this study demonstrates that TMEM119 is not exclusively expressed by microglia nor does it label all microglia, especially under cellular stress conditions. Since novel transgenic lines have been developed to label microglia using the TMEM119 promotor, downregulation of TMEM119 expression might interfere with the results and should, thus, be considered when working with these transgenic mouse models.

A New Understanding of TMEM119 as a Marker of Microglia

“…This suggests that TMEM119 protein is likely still involved in the activation of microglia, although the process of its downregulation in reactive microglia remains unclear. The present data in TBI ( Mercurio et al, 2022 ) are in agreement with the findings in the brain of patients with Alzheimer’s disease, in which the TMEM119 immunoreactivity is greatly reduced in the amyloid plaque-surrounding microglia and is often associated with a significant increase in Iba1 reactivity ( Swanson et al, 2020 ; Kenkhuis et al, 2022 ; Vankriekelsvenne et al, 2022 ). Moreover, the downregulation of TMEM119 protein in the contused area is in line with the findings at the sites of neurodegeneration where TMEM119 immunoreactivity is reduced in the disease-associated microglia ( Krasemann et al, 2017 ; Deczkowska et al, 2018 ; Satoh et al, 2019 ).…”

The spatiotemporal dynamics of microglia across the human lifespan

“…We complemented the IBA1 quantifications with an analysis of TMEM119 expression. This study may pose an opportunity to assess TMEM119, as there are conflicting reports in the literature about its validity as a bona fide microglial marker ( Bennett et al., 2016 ; Vankriekelsvenne et al., 2022 ). TMEM119 cell density changes tracked the pattern followed by IBA1 + cells between 9 and 16 pcw ( Figure 3 F).…”

Different Methods for Evaluating Microglial Activation Using Anti-Ionized Calcium-Binding Adaptor Protein-1 Immunohistochemistry in the Cuprizone Model

“…Secondly, while marker proteins have been identified which label microglia but not peripheral monocytes, for example, the transmembrane protein TMEM119 [ 48 ] or the purinergic receptor P2RY12, their expression is downregulated once microglia cells become activated [ 49 , 50 , 51 ]. Thirdly, while some marker proteins are expressed only by resting microglia cells (for example, TMEM119), some other marker proteins are exclusively expressed by activated microglia cells, such as the major histocompatibility complexes II (MHC-II) protein [ 48 , 52 , 53 ]. Of note, the MHC-II is not a specific protein in microglia as macrophages or B cells can also express MHC-II.…”