Microglia-Derived Small Extracellular Vesicles Reduce Glioma Growth by Modifying Tumor Cell Metabolism and Enhancing Glutamate Clearance through miR-124.

Carmela Serpe,Michela Relucenti,Pietro Familiari,Ludovica Iovino,Lucia Monaco,Ferdinando Scavizzi,Igea D’Agnano,Laura Civiero,Cristina Limatola,Marcello Raspa,Giuseppe Familiari,Myriam Catalano

doi:10.3390/cells10082066

Abstract

Brain homeostasis needs continuous exchange of intercellular information among neurons, glial cells, and immune cells, namely microglial cells. Extracellular vesicles (EVs) are active players of this process. All the cells of the body, including the brain, release at least two subtypes of EVs, the medium/large EVs (m/lEVs) and small EVs (sEVs). sEVs released by microglia play an important role in brain patrolling in physio-pathological processes. One of the most common and malignant forms of brain cancer is glioblastoma. Altered intercellular communications constitute a base for the onset and the development of the disease. In this work, we used microglia-derived sEVs to assay their effects in vitro on murine glioma cells and in vivo in a glioma model on C57BL6/N mice. Our findings indicated that sEVs carry messages to cancer cells that modify glioma cell metabolism, reducing lactate, nitric oxide (NO), and glutamate (Glu) release. sEVs affect Glu homeostasis, increasing the expression of Glu transporter Glt-1 on astrocytes. We demonstrated that these effects are mediated by miR-124 contained in microglia-released sEVs. The in vivo benefit of microglia-derived sEVs results in a significantly reduced tumor mass and an increased survival of glioma-bearing mice, depending on miR-124.

Highlights

Introduction distributed under the terms andTwo types of extracellular vesicles (EVs) have been described, and both kinds can be released from all the cells of the body, including the brain
Eleven genes were found to be upregulated in small EVs (sEVs) derived from LPS/IFNγ-treated microglia, Ccl2, Ccl3, Ccl5, Ccl7, Cd7, Cebpb, Cxcl9, Hif1a, Il1b, Rapgef2, and Tnf-α, while Ccl3, Il1b, Tnf-α, and Rapgef2 were downregulated in sEVs derived from interleukin 4 (IL-4)-treated microglia
The data of the immune system panel were validated by qRT-PCR: Il1b and Tnf-α genes were significantly upregulated in sEVs released by LPS/IFNγ-treated microglia and significantly downregulated in sEVs released by IL4-treated microglia, with respect to sEVs released by untreated cells (Figure S1A,B)

Summary

Introduction

Two types of extracellular vesicles (EVs) have been described, and both kinds can be released from all the cells of the body, including the brain. They comprise large EVs (m/lEVs) or microvesicles (MVs), originating from the outward bedding of the plasma membrane and rapidly released by the cells and small extracellular vesicles (sEVs) or conditions of the Creative Commons. EVs present different mechanisms of recognition and internalization into target cells [3], and both m/lEVs and sEVs are engulfed, merged or recognized by a receptor-mediated process [4]. Target cells could be both normal and neoplastic ones [6], and Exo-transferred content could exert, in gliomas, onco-suppression or onco-promotion [7]

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