TMEM119 marks a subset of microglia in the human brain

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.

Dominant role of microglial and macrophage innate immune responses in human ischemic infarcts

“…A similar conclusion has been reached in experimental models using radiation bone marrow chimeras (46,54). With further lesion maturation, the percentage of TMEM119 1 cells decreased, either suggesting a progressive loss of microglia derived macrophages in advanced lesions or a partial downregulation of TMEM119 in microglia after activation and transformation into macrophages (8,44).…”

“…Since fragmented nuclei of apoptosis can sometimes mimick nuclear morphology of granulocytes (14), we confirmed our data by immunocytochemistry for p22phox (NADPH-oxidase). This antigen is highly expressed in granulocytes (Figure 3 of TMEM119 is down-regulated but protein expression on the cell surface remains preserved (44). This is the case irrespective of the morphological phenotype of the cells, such as resting microglia, ameboid microglia or macrophage like cells.…”

“…This is the case irrespective of the morphological phenotype of the cells, such as resting microglia, ameboid microglia or macrophage like cells. In contrast, myeloid cells recruited into the lesions in the course of brain inflammation in rodents and humans do not express TMEM119 (4,44). (iv) States of microglia/macrophage activation: Recent studies defined the gene and protein expression profiles in different microglia stages.…”

Microglial Phenotypes and Functions in Multiple Sclerosis

“…TMEM119 is expressed by microglia but not by recruited monocytes in rodent CNS and in the human brain Bennett et al 2016;Satoh et al 2016). The marker TMEM119 was used to differentiate cells derived from the resident microglia pool from recruited macrophages in different stages of MS lesions.…”

Alterações transcriptômicas no hipocampo de ratos submetidos a um modelo experimental de epilepsia com insulto precipitante febril

“…Tmem119 codifica um marcador de micróglias residentes no cérebro humano (SATOH et al, 2016), enquanto a expressão de Cyp4f1 encontra-se aumentada em astrócitos hipocampais em ratos submetidos a um modelo de injúria cerebral (WANG et al, 2008).…”