title: Loss of CX3CR1 increases accumulation of inflammatory monocytes and promotes gliomagenesis.
abstract: 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.
authors.affiliation: Department of Neurosciences at Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Feng
authors.affiliation: Cellular Neurosciences, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Szulzewsky
authors.affiliation: Department of Neurosciences at Cleveland Clinic, Cleveland, Ohio, USA.|Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
authors.forename: Alexan
authors.initials: A
authors.lastname: Yerevanian
authors.affiliation: Department of Neurosciences at Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Neurosciences at Cleveland Clinic, Cleveland, Ohio, USA.|Department of Cardiology at Tübingen University School of Medicine, Tübingen, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Heinzmann
authors.affiliation: Department of Neurosciences at Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Rikke Darling
authors.initials: RD
authors.lastname: Rasmussen
authors.affiliation: Department of Neurosciences at Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Virginia
authors.initials: V
authors.lastname: Alvarez-Garcia
authors.affiliation: Department of Stem Cell Biology and Regenerative Medicine, Cleveland, Ohio, USA.
authors.forename: Yeonghwan
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Rammelkamp Center for Research, MetroHealth Center, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
authors.forename: Bingcheng
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Neurosciences at Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Tamagno
authors.affiliation: Department of Immunology at Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Immunology at Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
authors.affiliation: Cellular Neurosciences, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Kettenmann
authors.affiliation: Department of Neurosciences at Cleveland Clinic, Cleveland, Ohio, USA.|Neuroinflammation Research Center, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Ransohoff
authors.affiliation: Department of Neurosciences at Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Dolores
authors.initials: D
authors.lastname: Hambardzumyan
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000073883:CX3C Chemokine Receptor 1; D002460:Cell Line; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015151:Immunoblotting; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D018613:Microscopy, Confocal; D009000:Monocytes / Q000378:metabolism* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D019707:Receptors, Chemokine / Q000235:genetics* / Q000378:metabolism; D053573:Receptors, Interleukin-1 Type I / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; C471885:Cx3cr1 protein, mouse; C508590:IL1R1 protein, human; D053583:Interleukin-1beta; D019707:Receptors, Chemokine; D053573:Receptors, Interleukin-1 Type I; D048051:p38 Mitogen-Activated Protein Kinases
keywords: CX3CR1/CX3CL1 signaling; glioblastoma; microglia; monocyte