Tumor-associated reactive astrocytes aid the evolution of immunosuppressive environment in glioblastoma

Reactive astrocytes evolve after brain injury, inflammatory and degenerative diseases, whereby they undergo transcriptomic re-programming. In malignant brain tumors, their function and crosstalk to other components of the environment is poorly understood. Here we report a distinct transcriptional phenotype of reactive astrocytes from glioblastoma linked to JAK/STAT pathway activation. Subsequently, we investigate the origin of astrocytic transformation by a microglia loss-of-function model in a human organotypic slice model with injected tumor cells. RNA-seq based gene expression analysis of astrocytes reveals a distinct astrocytic phenotype caused by the coexistence of microglia and astrocytes in the tumor environment, which leads to a large release of anti-inflammatory cytokines such as TGFβ, IL10 and G-CSF. Inhibition of the JAK/STAT pathway shifts the balance of pro- and anti-inflammatory cytokines towards a pro-inflammatory environment. The complex interaction of astrocytes and microglia cells promotes an immunosuppressive environment, suggesting that tumor-associated astrocytes contribute to anti-inflammatory responses.

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Dieter Henrik Heiland, Vidhya M Ravi, Simon P Behringer, Jan Hendrik Frenking, Julian Wurm, Kevin Joseph, Nicklas W C Garrelfs, Jakob Strähle, Sabrina Heynckes, Jürgen Grauvogel, Pamela Franco, Irina Mader, Matthias Schneider, Anna-Laura Potthoff, Daniel Delev, Ulrich G Hofmann, Christian Fung, Jürgen Beck, Roman Sankowski, Marco Prinz, Oliver Schnell

期刊 Nat Commun
影响因子 16.6
起止号 2019 Jun 11;10(1):2541.
种属 Human
技术平台抗体芯片
应用领域神经系统
研究方向神经系统
细胞类型其它细胞
疾病类型胶质瘤
检测蛋白 Adiponectin/Acrp30,IFN-gamma,CCL2/MCP-1,Angiogenin,IGFBP-2,CCL7/MCP-3,Angiopoietin-1,IGFBP-3,M-CSF,Angiopoietin-2,IL-1 alpha/IL-1F1,MIF,Apolipoprotein A1,IL-1 beta/IL-1F2,CXCL9/MIG,BAFF/BLyS/TNFSF13B,IL-1ra/IL-1F3,CCL3/CCL4 MIP-1 alpha/beta,BDNF,IL-2,CCL20/MIP-3 alpha,CD14,IL-3,CCL19/MIP-3 beta,CD30,IL-4,MMP-9,CD31/PECAM-1,IL-5,Myeloperoxidase,CD40 Ligand/TNFSF5,IL-6,Osteopontin (OPN),Chitinase 3-like,IL-8,PDGF-AA,Complement Component C5/C5a,IL-10,PDGF-AB/BB,Complement Factor D,IL-11,Pentraxin 3/TSF-14,C-Reactive Protein/CRP,IL-12 p70,CXCL4/PF4,Cripto-1,IL-13,RAGE,Cystatin C,IL-15,CCL5/RANTES,Dkk-1,IL-16,RBP4,DPPIV/CD26,IL-17A,Relaxin-2,EGF,IL-18 BPa,Resistin,CXCL5/ENA-78,IL-19,CXCL12/SDF-1 alpha,Endoglin/CD105,IL-22,Serpin E1/PAI-1,EMMPRIN,IL-23,SHBG,Fas Ligand,IL-24,ST2/IL1 R4,FGF basic,IL-27,CCL17/TARC,KGF/FGF-7,IL-31,TFF3,FGF-19,IL-32 alpha/beta/gamma,TfR,Flt-3 Ligand,IL-33,TGF-alpha,G-CSF,IL-34,Thrombospondin-1,GDF-15,CXCL10/IP-10,TIM-1,GM-CSF,CXCL11/I-TAC,TNF-alpha,CXCL1/GRO alpha,Kallikrein 3/PSA,uPAR,Growth Hormone (GH),Leptin,VCAM-1,HGF,LIF,VEGF,ICAM-1/CD54,Lipocalin-2/NGAL,Vitamin D BP

Abstract

Reactive astrocytes evolve after brain injury, inflammatory and degenerative diseases, whereby they undergo transcriptomic re-programming. In malignant brain tumors, their function and crosstalk to other components of the environment is poorly understood. Here we report a distinct transcriptional phenotype of reactive astrocytes from glioblastoma linked to JAK/STAT pathway activation. Subsequently, we investigate the origin of astrocytic transformation by a microglia loss-of-function model in a human organotypic slice model with injected tumor cells. RNA-seq based gene expression analysis of astrocytes reveals a distinct astrocytic phenotype caused by the coexistence of microglia and astrocytes in the tumor environment, which leads to a large release of anti-inflammatory cytokines such as TGFβ, IL10 and G-CSF. Inhibition of the JAK/STAT pathway shifts the balance of pro- and anti-inflammatory cytokines towards a pro-inflammatory environment. The complex interaction of astrocytes and microglia cells promotes an immunosuppressive environment, suggesting that tumor-associated astrocytes contribute to anti-inflammatory responses.

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Abstract