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Front. Immunol. | doi: 10.3389/fimmu.2018.02750

CXCL16/CXCR6 axis drives microglia/macrophages phenotype in physiological conditions and plays a crucial role in glioma

Francesca Lepore1,  Giuseppina D'Alessandro2, Antonio Santoro1, Vincenzo Esposito2,  Cristina Limatola3* and  Flavia Trettel1*
  • 1Department of Physiology and Pharmacology, Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, La Sapienza University of Rome, Italy
  • 2Istituto Neurologico Mediterraneo (IRCCS), Italy
  • 3Department of Physiology and Pharmacology, Sapienza University of Rome, Italy

Microglia are patrolling cells that sense changes in 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 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 towards anti-inflammatory phenotype, also restraining microglia polarization towards an inflammatory phenotype upon LPS and IFNstimulation. In the context of glioma, we demonstrate that CXCL16 released by tumor cells is determinant in promoting glioma associated microglia/macrophages (GAMs) modulation towards an anti-inflammatory/pro-tumor phenotype, and that, cxcr6ko mice brain-transplanted with GL261 glioma survive longer compared to wild-type mice. We also describe that CXCL16/CXCR6 signaling acts directly on 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.

Keywords: CXCL16/CXCR6, Tumor Microenvironment, Microglia, Glioma, Neuroinflammation

Received: 04 Aug 2018; Accepted: 08 Nov 2018.

Edited by:

Brian A. Zabel, Palo Alto Veterans Institute for Research, United States

Reviewed by:

Peter A. Ward, University of Michigan, United States
Paola Bezzi, Université de Lausanne, Switzerland  

Copyright: © 2018 Lepore, D'Alessandro, Santoro, Esposito, Limatola and Trettel. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Prof. Cristina Limatola, Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy, Cristina.limatola@uniroma1.it
Prof. Flavia Trettel, La Sapienza University of Rome, Department of Physiology and Pharmacology, Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Rome, 00185, Italy, flavia.trettel@uniroma1.it