characteristics of the alternative phenotype of microgliamacrophages and its modulation in experimental gliomasmicrogliamacrophages替代表型的特点及其调制实验神经胶质瘤.pdfVIP

Characteristics of the Alternative Phenotype of Microglia/Macrophages and its Modulation in Experimental Gliomas Konrad Gabrusiewicz, Aleksandra Ellert-Miklaszewska, Maciej Lipko, Malgorzata Sielska, Marta Frankowska, Bozena Kaminska* Laboratory of Transcription Regulation, Nencki Institute of Experimental Biology, Warsaw, Poland 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