Omar Dildar a Dzaye, F. Hu, K. Derkow, Verena Haage, P. Euskirchen, C. Harms, S. Lehnardt, M. Synowitz, S. Wolf, H. Kettenmann
{"title":"胶质瘤干细胞而非大块胶质瘤细胞通过toll样受体4信号上调小胶质细胞/脑巨噬细胞IL-6分泌","authors":"Omar Dildar a Dzaye, F. Hu, K. Derkow, Verena Haage, P. Euskirchen, C. Harms, S. Lehnardt, M. Synowitz, S. Wolf, H. Kettenmann","doi":"10.1093/jnen/nlw016","DOIUrl":null,"url":null,"abstract":"Peripheral macrophages and resident microglia constitute the dominant glioma-infiltrating cells. The tumor induces an immunosuppressive and tumor-supportive phenotype in these glioma-associated microglia/brain macrophages (GAMs). A subpopulation of glioma cells acts as glioma stem cells (GSCs). We explored the interaction between GSCs and GAMs. Using CD133 as a marker of stemness, we enriched for or deprived the mouse glioma cell line GL261 of GSCs by fluorescence-activated cell sorting (FACS). Over the same period of time, 100 CD133+ GSCs had the capacity to form a tumor of comparable size to the ones formed by 10,000 CD133- GL261 cells. In IL-6-/- mice, only tumors formed by CD133+ cells were smaller compared with wild type. After stimulation of primary cultured microglia with medium from CD133-enriched GL261 glioma cells, we observed an selective upregulation in microglial IL-6 secretion dependent on Toll-like receptor (TLR) 4. Our results show that GSCs, but not the bulk glioma cells, initiate microglial IL-6 secretion via TLR4 signaling and that IL-6 regulates glioma growth by supporting GSCs. Using human glioma tissue, we could confirm the finding that GAMs are the major source of IL-6 in the tumor context.","PeriodicalId":16434,"journal":{"name":"Journal of Neuropathology & Experimental Neurology","volume":"49 1","pages":"429–440"},"PeriodicalIF":0.0000,"publicationDate":"2016-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"60","resultStr":"{\"title\":\"Glioma Stem Cells but Not Bulk Glioma Cells Upregulate IL-6 Secretion in Microglia/Brain Macrophages via Toll-like Receptor 4 Signaling\",\"authors\":\"Omar Dildar a Dzaye, F. Hu, K. Derkow, Verena Haage, P. Euskirchen, C. Harms, S. Lehnardt, M. Synowitz, S. Wolf, H. Kettenmann\",\"doi\":\"10.1093/jnen/nlw016\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Peripheral macrophages and resident microglia constitute the dominant glioma-infiltrating cells. The tumor induces an immunosuppressive and tumor-supportive phenotype in these glioma-associated microglia/brain macrophages (GAMs). A subpopulation of glioma cells acts as glioma stem cells (GSCs). We explored the interaction between GSCs and GAMs. Using CD133 as a marker of stemness, we enriched for or deprived the mouse glioma cell line GL261 of GSCs by fluorescence-activated cell sorting (FACS). Over the same period of time, 100 CD133+ GSCs had the capacity to form a tumor of comparable size to the ones formed by 10,000 CD133- GL261 cells. In IL-6-/- mice, only tumors formed by CD133+ cells were smaller compared with wild type. After stimulation of primary cultured microglia with medium from CD133-enriched GL261 glioma cells, we observed an selective upregulation in microglial IL-6 secretion dependent on Toll-like receptor (TLR) 4. Our results show that GSCs, but not the bulk glioma cells, initiate microglial IL-6 secretion via TLR4 signaling and that IL-6 regulates glioma growth by supporting GSCs. Using human glioma tissue, we could confirm the finding that GAMs are the major source of IL-6 in the tumor context.\",\"PeriodicalId\":16434,\"journal\":{\"name\":\"Journal of Neuropathology & Experimental Neurology\",\"volume\":\"49 1\",\"pages\":\"429–440\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2016-05-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"60\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Neuropathology & Experimental Neurology\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1093/jnen/nlw016\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Neuropathology & Experimental Neurology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1093/jnen/nlw016","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
Glioma Stem Cells but Not Bulk Glioma Cells Upregulate IL-6 Secretion in Microglia/Brain Macrophages via Toll-like Receptor 4 Signaling
Peripheral macrophages and resident microglia constitute the dominant glioma-infiltrating cells. The tumor induces an immunosuppressive and tumor-supportive phenotype in these glioma-associated microglia/brain macrophages (GAMs). A subpopulation of glioma cells acts as glioma stem cells (GSCs). We explored the interaction between GSCs and GAMs. Using CD133 as a marker of stemness, we enriched for or deprived the mouse glioma cell line GL261 of GSCs by fluorescence-activated cell sorting (FACS). Over the same period of time, 100 CD133+ GSCs had the capacity to form a tumor of comparable size to the ones formed by 10,000 CD133- GL261 cells. In IL-6-/- mice, only tumors formed by CD133+ cells were smaller compared with wild type. After stimulation of primary cultured microglia with medium from CD133-enriched GL261 glioma cells, we observed an selective upregulation in microglial IL-6 secretion dependent on Toll-like receptor (TLR) 4. Our results show that GSCs, but not the bulk glioma cells, initiate microglial IL-6 secretion via TLR4 signaling and that IL-6 regulates glioma growth by supporting GSCs. Using human glioma tissue, we could confirm the finding that GAMs are the major source of IL-6 in the tumor context.