TMEM119 marks a subset of microglia in the human brain
Jun-ichi Satoh1, Yoshihiro Kino1, Naohiro Asahina1
1Department of Bioinformatics and Molecular Neuropathology, Meiji Pharmaceutical University, Tokyo, Japan.
Abstract:
Microglia are resident myeloid cells of the central nervous system (CNS), activated in the brains of various neurological diseases. Microglia are ontogenetically and functionally distinct from monocyte-derived macrophages that infiltrate the CNS under pathological conditions. However, a lack of specific markers that distinguish resident microglia from circulating blood-derived macrophages in human brain tissues hampers accurate evaluation of microglial contributions to the human brain pathology. By comparative analysis of five comprehensive microglial transcriptome datasets, we identified an evolutionarily conserved protein TMEM119 as the most promising candidate for human microglial markers. TMEM119 was expressed on immortalized human microglia, in which the expression levels were not elevated by exposure to lipopolysaccharide, IFNγ, IL-4, IL-13 or TGFβ1. Notably, TMEM119 immunoreactivity was expressed exclusively on a subset of Iba1(+) CD68(+) microglia with ramified and amoeboid morphologies in the brains of neurodegenerative diseases, such as Alzheimer's disease (AD), whereas Iba1(+) CD68(+) infiltrating macrophages do not express TMEM119 in demyelinating lesions of multiple sclerosis and necrotic lesions of cerebral infarction. TMEM119 mRNA levels were elevated in AD brains, although the protein levels were not significantly different between AD and non-AD cases by western blot and morphometric analyses. TMEM119-positive microglia did not consistently express polarized markers for M1 (CD80) or M2 (CD163, CD209) in AD brains. These results suggest that TMEM119 serves as a reliable microglial marker that discriminates resident microglia from blood-derived macrophages in the human brain.
Insights
TMEM119 is a novel protein marker that reliably distinguishes resident microglia from infiltrating macrophages in the human brain. This discovery aids in understanding microglial roles in neurological diseases like Alzheimer's disease.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia, the central nervous system's resident myeloid cells, are activated in various neurological diseases.
- Distinguishing microglia from infiltrating blood-derived macrophages in human brain tissue is challenging due to a lack of specific markers.
- Accurate differentiation is crucial for evaluating microglial contributions to human brain pathology.
Purpose of the Study:
- To identify a reliable marker for human microglia that differentiates them from infiltrating macrophages.
- To validate TMEM119 as a specific marker for resident microglia in the human brain.
Main Methods:
- Comparative analysis of five human microglial transcriptome datasets.
- Identification and validation of TMEM119 as a potential microglial marker.
- Immunohistochemical analysis of TMEM119 expression in human brain tissues from Alzheimer's disease, multiple sclerosis, and cerebral infarction.
- Western blot and morphometric analyses to assess TMEM119 protein levels.
Main Results:
- TMEM119 was identified as the most promising candidate marker for human microglia.
- TMEM119 expression was confirmed in immortalized human microglia and not upregulated by inflammatory stimuli.
- TMEM119 immunoreactivity was exclusively found on resident microglia in Alzheimer's disease brains.
- Infiltrating macrophages in multiple sclerosis and cerebral infarction lesions lacked TMEM119 expression.
- TMEM119 mRNA levels were elevated in Alzheimer's disease brains, but protein levels showed no significant difference between AD and non-AD cases.
- TMEM119-positive microglia in AD brains did not consistently express M1 or M2 polarized markers.
Conclusions:
- TMEM119 is a reliable and evolutionarily conserved marker for resident human microglia.
- TMEM119 enables discrimination between microglia and infiltrating macrophages in the human brain.
- This marker facilitates a more accurate assessment of microglial roles in human neurological diseases.
