CXCL16/CXCR6 Axis Drives Microglia/Macrophages Phenotype in Physiological Conditions and Plays a Crucial Role in Glioma.

Francesca Lepore,Vincenzo Esposito,Flavia Trettel,Giuseppina D'Alessandro,Cristina Limatola,Antonio Santoro,Fabrizio Antonangeli

doi:10.3389/fimmu.2018.02750

Abstract

Microglia are patrolling cells that sense changes in the brain microenvironment and respond acquiring distinct phenotypes that can be either beneficial or detrimental for brain homeostasis. Anti-inflammatory microglia release soluble factors that might promote brain repair; however, in glioma, anti-inflammatory microglia dampen immune response and promote a brain microenvironment that foster tumor growth and invasion. The chemokine CXCL16 is expressed in the brain, where it is neuroprotective against brain ischemia, and it has been found to be over-expressed in glioblastoma (GBM). Considering that CXCL16 specific receptor CXCR6 is diffusely expressed in the brain including in microglia cells, we wanted to investigate the role of CXCL16 in the modulation of microglia cell activity and phenotype, and in the progression of glioma. Here we report that CXCL16 drives microglia polarization toward an anti-inflammatory phenotype, also restraining microglia polarization toward an inflammatory phenotype upon LPS and IFNγ stimulation. In the context of glioma, we demonstrate that CXCL16 released by tumor cells is determinant in promoting glioma associated microglia/macrophages (GAMs) modulation toward an anti-inflammatory/pro-tumor phenotype, and that cxcr6ko mice, orthotopically implanted into the brain with GL261 glioma cells,survive longer compared to wild-type mice. We also describe that CXCL16/CXCR6 signaling acts directly on mouse glioma cells, as well as human primary GBM cells, promoting tumor cell growth, migration and invasion. All together these data suggest that CXCL16 signaling could represent a good target to modulate microglia phenotype in order to restrain inflammation or to limit glioma progression.

Highlights

Modification of local brain microenvironment can be sensed by microglia cells, which respond to preserve brain homeostasis, or to exacerbate brain damage
Since we have shown that CXCL16 is neuroprotective in ischemia [11, 12], and neuroinflammation plays a role in brain damage following ischemic insult [30, 31], we considered the possibility that CXCL16, acting on CXCR6 expressed by microglia cells [11], might provide protective effects modulating microglia phenotype
We measured the release of nitric oxide (NO) and IL-1β by microglia cells treated with vehicle or LPS + IFNγ, in the presence or not of CXCL16: as shown in Figures 1F,G, the release of Nitric Oxide (NO) (n = 7, p < 0.05; One-way ANOVA followed by Holm–Sidak post-hoc test) and IL1β (n = 4, p < 0.05; One-way ANOVA followed by Holm–Sidak post-hoc test) induced by LPS + IFNγ was significantly reduced by treatment with CXCL16

Summary

Introduction

Modification of local brain microenvironment can be sensed by microglia cells, which respond to preserve brain homeostasis, or to exacerbate brain damage. Non-tumor cells of the brain parenchyma, such as astrocytes, endothelial cells, and microglia, as well as infiltrating peripheral immune cells, sense glioma, and contribute to the formation of a tumor niche that provides a crucial environment for glioma progression. In this context, the cross-talk between tumor cells and glioma associated microglia/macrophages (GAMs) leads to GAMs polarization toward an anti-inflammatory, immunosuppressive, pro-invasive phenotype that support tumor growth and invasion [18]

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Results

Conclusion