Microglia in Close Vicinity of Glioma Cells: Correlation Between Phenotype and Metabolic Alterations

Abstract

Microglia are immune cells within the central nervous system. In brain-developing tumors, gliomas are able to silence the defense and immune functions of microglia, a phenomenon which strongly contributes to tumor progression and treatment resistance. Being activated and highly motile, microglia infiltrate tumors and secrete macrophagic chemoattractant factors. Thereafter, the tumor cells shut down their immune properties and stimulate the microglia to release tumor growth-promoting factors. The result of such modulation is that a kind of symbiosis occurs between microglia and tumor cells, in favor of tumor growth. However, little is known about microglial phenotype and metabolic modifications in a tumoral environment. Co-cultures were performed using CHME5 microglia cells grown on collagen beads or on coverslips and placed on monolayer of C6 cells, limiting cell/cell contacts. Phagocytic behavior and expression of macrophagic and cytoskeleton markers were monitored. Respiratory properties and energetic metabolism were also studied with regard to the activated phenotype of microglia. In co-cultures, transitory modifications of microglial morphology and metabolism were observed linked to a concomitant transitory increase of phagocytic properties. Therefore, after 1 h of co-culture, microglia were activated but when longer in contact with tumor cells, phagocytic properties appear silenced. Like the behavior of the phenotype, microglial respiration showed a transitory readjustment although the mitochondria maintained their perinuclear relocation. Nevertheless, the energetic metabolism of the microglia was altered, suggesting a new energetic steady state. The results clearly indicate that like the depressed immune properties, the macrophagic and metabolic status of the microglia is quickly driven by the glioma environment, despite short initial phagocytic activation. Such findings question the possible contribution of diffusible tumor factors to the microglial metabolism.

The Controversial Role of Microglia in Malignant Gliomas

“…A direct correlation has been shown between the immunogenicity of glioma tumor cells and the GAM content and their antigen-presenting function [78, 79]. In addition, the metabolic status of the microglia is altered by the glioma environment [80]. Abundant amounts of ATP released by the glioma have been suggested to trigger P2X 7 R signaling, resulting in increase of MIP-1 α (macrophage inflammatory protein-1 α ) and MCP-1 (monocyte chemoattractant protein-1) in GAMs [81].…”

The Role of Microglia and Matrix Metalloproteinases Involvement in Neuroinflammation and Gliomas

“…The antitumor properties, namely glioma-cytotoxic effects of microglia, could only be shown in vitro so far [147, 148]. Favoring gliomas' growth could be due to a suppression and/or control of microglial cells by glioma cells and glioma-derived molecules (e.g., their loss of phagocytic function [149]. It was also suggested that, under the influence of glioma cells, microglia develop a different, noninflammatory phenotype suppressing their defense properties [139, 144, 150].…”

Macrophages and Microglia in Brain Malignancies

“…They did not support T cell proliferative responses, and they did not constitutively express significant levels of inflammatory or anti-inflammatory cytokines when tested ex vivo. Phagocytic function was detectable in these experiments, however, other studies on rat microglia indicated that continued presence of glioma cells may inhibit this process (Voisin et al, 2010).…”