Laboratory of Molecular Neurobiology, Neurobiology Center, The Nencki Institute of Experimental Biology, 3 Pasteur str., Warsaw, Poland.
Glia. 2013 Jul;61(7):1178-90. doi: 10.1002/glia.22510. Epub 2013 May 7.
Microglia are myeloid cells residing in the central nervous system that participate in inflammatory responses and could promote injury and repair. Gliomas attract microglia and polarize them into tumor-supporting cells that participate in matrix remodeling, invasion, angiogenesis, and suppression of adaptive immunity. Although signaling pathways and critical regulators underlying classical inflammation are well established, signal transduction and transcriptional circuits underlying the alternative activation of microglia are poorly known. Using primary rat microglial cultures exposed to glioma conditioned medium or lipopolysaccharide (LPS), we demonstrate that microglia adapt different fates and polarize into pro-inflammatory or alternatively activated cells. Glioma-derived factors increased cell motility, phagocytosis, and sustained proliferation of microglial cells that was mediated by enhanced focal adhesion kinase and PI-3K/Akt signaling. The signals from glioma cells induced ERK and p38 MAPK but not JNK signaling and failed to activate pro-inflammatory Stat1 and NFκB signaling in microglial cells. Transcriptome analysis of microglial cultures at 6 h after exposure to glioma-conditioned medium or LPS revealed different patterns of gene expression. Glioma-induced activation was associated with induction of genes coding for ID (inhibitor of DNA binding) 1/3 and c-Myc, markers of the alternative phenotype Arg1, MT1-MMP, CXCL14, and numerous cytokines/chemokines implicated in immune cell trafficking. Many classical inflammation-related genes and signaling pathways failed to be induced. Our study indicates for the first time molecular pathways that direct microglia toward the pro-invasive, immunosuppressive phenotype.
小胶质细胞是存在于中枢神经系统中的髓样细胞，参与炎症反应，并可能促进损伤和修复。神经胶质瘤吸引小胶质细胞，并将其极化成为支持肿瘤的细胞，参与基质重塑、侵袭、血管生成和适应性免疫抑制。尽管经典炎症的信号通路和关键调节因子已经得到很好的研究，但小胶质细胞的替代激活的信号转导和转录回路知之甚少。使用暴露于神经胶质瘤条件培养基或脂多糖（LPS）的原代大鼠小胶质细胞培养物，我们证明小胶质细胞适应不同的命运，并极化为促炎或替代激活的细胞。神经胶质瘤来源的因子增加了小胶质细胞的迁移、吞噬和持续增殖，这是由增强的焦点黏附激酶和 PI-3K/Akt 信号介导的。来自神经胶质瘤细胞的信号诱导 ERK 和 p38 MAPK，但不诱导 JNK 信号，并且不能在小胶质细胞中激活促炎 Stat1 和 NFκB 信号。暴露于神经胶质瘤条件培养基或 LPS 6 小时后小胶质细胞培养物的转录组分析揭示了不同的基因表达模式。神经胶质瘤诱导的激活与 ID（DNA 结合抑制剂）1/3 和 c-Myc 的基因表达诱导相关，这是替代表型 Arg1、MT1-MMP、CXCL14 和许多参与免疫细胞迁移的细胞因子/趋化因子的标志物。许多经典炎症相关基因和信号通路未能被诱导。我们的研究首次表明了指导小胶质细胞向促侵袭、免疫抑制表型的分子途径。
