CX3CR1 promotes recruitment of human glioma-infiltrating microglia/macrophages (GIMs).
The transmembrane chemokine CX3CL1 and its receptor CX3CR1 are thought to be involved in the trafficking of immune cells during an immune response and in the pathology of various human diseases including cancer. However, little is known about the expression and function of CX3CR1 in human glioma-infiltrating microglia/macrophages (GIMs), representing the major cellular stroma component of highly malignant gliomas. Here, we show that CX3CR1 is overexpressed at both the mRNA and protein level in solid human astrocytomas of different malignancy grades and in glioblastomas. CX3CR1 was localized in ionized calcium-binding adapter molecule 1 (Iba1) and CD11b/c positive GIMs in situ as shown by fluorescence microscopy. In accordance with this, freshly isolated human GIM-enriched fractions separated by CD11b MACS technology displayed high Iba1 and CX3CR1 mRNA expression levels in vitro. Moreover, cultured human GIMs responded to CX3CL1-triggered activation of CX3CR1 with adhesion and migration in vitro. Besides an increase in motility, CX3CL1 also enhanced expression of matrix metalloproteases 2, 9, and 14 in GIM fractions in vitro. These data indicate that the CX3CL1/CX3CR1 system has a crucial tumor-promoting role in human glioblastomas via its impact on glioma-infiltrating immune subsets.
Held-Feindt
Janka
J
Department of Neurosurgery, University Medical Center Schleswig-Holstein UKSH, Kiel, Germany. held-feindtj@nch.uni-kiel.de
Hattermann
Kirsten
K
Müerköster
Susanne Sebens
SS
Wedderkopp
Hanna
H
Knerlich-Lukoschus
Friederike
F
Ungefroren
Hendrik
H
Mehdorn
H Maximilian
HM
Mentlein
Rolf
R
D015153:Blotting, Western; D001921:Brain / Q000166:cytology / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D039481:CD11b Antigen / Q000235:genetics / Q000378:metabolism; D039521:CD11c Antigen / Q000235:genetics / Q000378:metabolism; D000073883:CX3C Chemokine Receptor 1; D002135:Calcium-Binding Proteins; D016022:Case-Control Studies; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008840:Microfilament Proteins; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018874:Spheroids, Cellular / Q000378:metabolism
C112986:AIF1 protein, human; D039481:CD11b Antigen; D039521:CD11c Antigen; D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; C509295:ITGAM protein, human; D008840:Microfilament Proteins; D012333:RNA, Messenger; D019707:Receptors, Chemokine; D020782:Matrix Metalloproteinases