Loss of CX3CR1 increases accumulation of inflammatory monocytes and promotes gliomagenesis
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Xi Feng1, Frank Szulzewsky2,*, Alexan Yerevanian1,3,*, Zhihong Chen1, David Heinzmann1,4, Rikke Darling Rasmussen1, Virginia Alvarez-Garcia1, Yeonghwan Kim5, Bingcheng Wang6, Ilaria Tamagno1, Hao Zhou7, Xiaoxia Li7, Helmut Kettenmann2, Richard M. Ransohoff1,8 and Dolores Hambardzumyan1
1 Department of Neurosciences at Cleveland Clinic, Cleveland, Ohio, USA
2 Cellular Neurosciences, Max Delbrück Center for Molecular Medicine, Berlin, Germany
3 Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
4 Department of Cardiology at Tübingen University School of Medicine, Tübingen, Germany
5 Department of Stem Cell Biology and Regenerative Medicine, Cleveland, Ohio, USA
6 Rammelkamp Center for Research, MetroHealth Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
7 Department of Immunology at Cleveland Clinic, Cleveland, Ohio, USA
8 Neuroinflammation Research Center, Cleveland Clinic, Cleveland, Ohio, USA
* These authors have contributed equally to this work
Dolores Hambardzumyan, email:
Keywords: CX3CR1/CX3CL1 signaling, glioblastoma, microglia, monocyte
Received: January 19, 2015 Accepted: March 10, 2015 Published: March 30, 2015
The most abundant populations of non-neoplastic cells in the glioblastoma (GBM) microenvironment are resident microglia, macrophages and infiltrating monocytes from the blood circulation. The mechanisms by which monocytes infiltrate into GBM, their fate following infiltration, and their role in GBM growth are not known. Here we tested the hypothesis that loss of the fractalkine receptor CX3CR1 in microglia and monocytes would affect gliomagenesis. Deletion of Cx3cr1 from the microenvironment resulted in increased tumor incidence and shorter survival times in glioma-bearing mice. Loss of Cx3cr1 did not affect accumulation of microglia/macrophages in peri-tumoral areas, but instead indirectly promoted the trafficking of CD11b+CD45hiCX3CR1lowLy-6ChiLy-6G-F4/80-/low circulating inflammatory monocytes into the CNS, resulting in their increased accumulation in the perivascular area. Cx3cr1-deficient microglia/macrophages and monocytes demonstrated upregulation of IL1β expression that was inversely proportional to Cx3cr1 gene dosage. The Proneural subgroup of the TCGA GBM patient dataset with high IL1β expression showed shorter survival compared to patients with low IL1β. IL1β promoted tumor growth and increased the cancer stem cell phenotype in murine and human Proneural glioma stem cells (GSCs). IL1β activated the p38 MAPK signaling pathway and expression of monocyte chemoattractant protein (MCP-1/CCL2) by tumor cells. Loss of Cx3cr1 in microglia in a monocyte-free environment had no impact on tumor growth and did not alter microglial migration. These data suggest that enhancing signaling to CX3CR1 or inhibiting IL1β signaling in intra-tumoral macrophages can be considered as potential strategies to decrease the tumor-promoting effects of monocytes in Proneural GBM.
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