title: Characteristics of the alternative phenotype of microglia/macrophages and its modulation in experimental gliomas.
abstract: Microglia (brain resident macrophages) accumulate in malignant gliomas and instead of initiating the anti-tumor response, they switch to a pro-invasive phenotype, support tumor growth, invasion, angiogenesis and immunosuppression by release of cytokines/chemokines and extracellular matrix proteases. Using immunofluorescence and flow cytometry, we demonstrate an early accumulation of activated microglia followed by accumulation of macrophages in experimental murine EGFP-GL261 gliomas. Those cells acquire the alternative phenotype, as evidenced by evaluation of the production of ten pro/anti-inflammatory cytokines and expression profiling of 28 genes in magnetically-sorted CD11b(+) cells from tumor tissues. Furthermore, we show that infiltration of implanted gliomas by amoeboid, Iba1-positive cells can be reduced by a systematically injected cyclosporine A (CsA) two or eight days after cell inoculation. The up-regulated levels of IL-10 and GM-CSF, increased expression of genes characteristic for the alternative and pro-invasive phenotype (arg-1, mt1-mmp, cxcl14) in glioma-derived CD11b(+) cells as well as enhanced angiogenesis and tumor growth were reduced in CsA-treated mice. Our findings define for the first time kinetics and biochemical characteristics of glioma-infiltrating microglia/macrophages. Inhibition of the alternative activation of tumor-infiltrating macrophages significantly reduced tumor growth. Thus, blockade of microglia/macrophage infiltration and their pro-invasive functions could be a novel therapeutic strategy in malignant gliomas.
authors: Laboratory of Transcription Regulation, Nencki Institute of Experimental Biology, Warsaw, Poland.
authors: Konrad
authors: K
authors: Gabrusiewicz
authors: Aleksandra
authors: A
authors: Ellert-Miklaszewska
authors: Maciej
authors: M
authors: Lipko
authors: Malgorzata
authors: M
authors: Sielska
authors: Marta
authors: M
authors: Frankowska
authors: Bozena
authors: B
authors: Kaminska
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D019743:Chemokines, CXC / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005910:Glioma / Q000378:metabolism* / Q000473:pathology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D007150:Immunohistochemistry; D016753:Interleukin-10 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism / Q000473:pathology*
chemical_list: D039481:CD11b Antigen; C517518:CXCL14 protein, mouse; D019743:Chemokines, CXC; C507096:Mmp14 protein, mouse; D016753:Interleukin-10; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D020778:Matrix Metalloproteinase 2; D053511:Matrix Metalloproteinase 14