TSPO Ligands Modulate Human Myeloid Cell Phagocytosis

Identification: Phillips, Alexandra


Description

TSPO Ligands Modulate Human Myeloid Cell Phagocytosis
 
Alexandra Phillips1, Maria Weinert1, David Owen1, Paul Matthews1
1Division of Brain Sciences, Department of Medicine Hammersmith Hospital, Imperial College London, London, UK
 
The 18kDa Translocator Protein (TSPO) is a highly conserved outer mitochondrial membrane protein, which is expressed by most cell types but is found at particularly high levels in myeloid cells. In the CNS, TSPO is primarily expressed by microglia. In vitro and in vivo studies have shown that TSPO ligands bias myeloid cells towards immunosuppressive, reparative phenotypes and reduce clinical severity and inflammatory pathology in the rodent model of multiple sclerosis (MS). However, the vast majority of such data has been performed in rodent myeloid cells, which differ markedly in TSPO regulation relative to human myeloid cells.
Microglial phagocytosis is critical for the removal of debris from the CNS, whilst also promoting anti-inflammatory responses. Variants in phagocytosis-associated genes have been implicated in a range of neurodegenerative diseases including Alzheimer's disease and MS, demonstrating the importance of this myeloid cell function in CNS homeostasis. Indeed, macrophages derived from MS patient monocytes have deficits in phagocytosis relative to healthy donor cells.
In this study, human peripheral blood monocytes were isolated by ficoll gradient and CD14 magnetic bead separation from healthy control whole blood samples. Monocytes were pre-treated with the TSPO ligands XBD173 and etifoxine at concentrations commensurate with TSPO binding affinity measured in human samples. Uptake of fluorescently-labelled zymosan particles was measured by flow cytometry. We show that these TSPO ligands increase human monocyte phagocytosis relative to vehicle controls, both in terms of the number of cells which take up zymosan, and the amount taken up per cell.
These findings indicate that pharmacologically relevant doses of TSPO ligands modulate a myeloid cell function associated with a neuroprotective phenotype and thus could form the basis of novel therapies for neurodegeneration.
 
This research is funded by the MRC.
 

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