title: Resident microglia, and not peripheral macrophages, are the main source of brain tumor mononuclear cells.
abstract: Gliomas consist of multiple cell types, including an abundant number of microglia and macrophages, whereby their impact on tumor progression is controversially discussed. To understand their unique functions and consequently manipulate either microglia or macrophages in therapeutic approaches, it is essential to discriminate between both cell populations. Because of the lack of specific markers, generally total body irradiated chimeras with labeled bone marrow cells were used to identify infiltrated cells within the brain. However, total body irradiation (TBI) affects the blood-brain barrier integrity, which in turn potentially facilitates immune cell infiltration. In this study, changes on the blood-brain barrier were avoided using head-protected irradiation (HPI). Head protection and total body irradiated chimeras exhibited similar reconstitution levels of the myeloid cell lineage in the blood, enabling the comparable analyses of brain infiltrates. We demonstrate that the HPI model impeded a massive unspecific influx of donor-derived myeloid cells into naive as well as tumor-bearing brains. Moreover, experimental artifacts such as an enlarged distribution of infiltrated cells and fourfold increased tumor volumes are prevented in head-protected chimeras. In addition, our data evidenced for the first time that microglia are able to up-regulate CD45 and represent an inherent part of the CD45(high) population in the tumor context. All in all, HPI allowed for the unequivocal distinction between microglia and macrophages without alterations of tumor biology and consequently permits a detailed and realistic description of the myeloid cell composition in gliomas.
authors.affiliation: Department of Neurosurgery, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Annett
authors.initials: A
authors.lastname: Müller
authors.affiliation: Department of Neurosurgery, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Susan
authors.initials: S
authors.lastname: Brandenburg
authors.affiliation: Department of Neurosurgery, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Kati
authors.initials: K
authors.lastname: Turkowski
authors.affiliation: Center for Stroke Research, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Müller
authors.affiliation: Department of Neurosurgery, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Vajkoczy
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D039481:CD11b Antigen / Q000378:metabolism; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D005910:Glioma / Q000378:metabolism / Q000473:pathology*; D006257:Head / Q000528:radiation effects; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008264:Macrophages / Q000473:pathology*; D008297:Male; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism / Q000473:pathology*; D008856:Microscopy, Fluorescence; D009368:Neoplasm Transplantation / Q000379:methods; D011835:Radiation Protection / Q000379:methods; D014916:Whole-Body Irradiation / Q000379:methods
chemical_list: D039481:CD11b Antigen; D017493:Leukocyte Common Antigens
keywords: CD45 expression; chimerism; glioma; head-protected irradiation; microglia/macrophages