Glial cell line‐derived neurotrophic factor increases matrix metallopeptidase 9 and 14 expression in microglia and promotes microglia‐mediated glioma progression

Huang, Yimin; Zhang, Baole; Haneke, Hannah; Haage, Verena; Lubas, Malgorzata; Yang, Yuan; Xia, Peng‐Fei; Motta, Edyta; Nanvuma, Cynthia; Dzaye, Omar; Hu, Feng; Kettenmann, Helmut

doi:10.1002/jnr.24768

Cited by 13 publications

(8 citation statements)

References 31 publications

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“…Neurotrophic factors have also been widely reported in gliomas. For example, GDNF which is released by glioma cells can promote tumor growth, an action that is dependent on the presence of microglia ( 56 ). The development of immunotherapy has triggered an increasing number of investigations into the clinical efficacy of targeting immune checkpoints, including early diagnosis, combination therapy, and treatment prediction in patients with various types of tumors.…”

Section: Discussionmentioning

confidence: 99%

Identification and validation of neurotrophic factor-related gene signatures in glioblastoma and Parkinson’s disease

et al. 2023

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BackgroundGlioblastoma multiforme (GBM) is the most common cancer of the central nervous system, while Parkinson’s disease (PD) is a degenerative neurological condition frequently affecting the elderly. Neurotrophic factors are key factors associated with the progression of degenerative neuropathies and gliomas.MethodsThe 2601 neurotrophic factor-related genes (NFRGs) available in the Genecards portal were analyzed and 12 NFRGs with potential roles in the pathogenesis of Parkinson’s disease and the prognosis of GBM were identified. LASSO regression and random forest algorithms were then used to screen the key NFRGs. The correlation of the key NFRGs with immune pathways was verified using GSEA (Gene Set Enrichment Analysis). A prognostic risk scoring system was constructed using LASSO (Least absolute shrinkage and selection operator) and multivariate Cox risk regression based on the expression of the 12 NFRGs in the GBM cohort from The Cancer Genome Atlas (TCGA) database. We also investigated differences in clinical characteristics, mutational landscape, immune cell infiltration, and predicted efficacy of immunotherapy between risk groups. Finally, the accuracy of the model genes was validated using multi-omics mutation analysis, single-cell sequencing, QT-PCR, and HPA.ResultsWe found that 4 NFRGs were more reliable for the diagnosis of Parkinson’s disease through the use of machine learning techniques. These results were validated using two external cohorts. We also identified 7 NFRGs that were highly associated with the prognosis and diagnosis of GBM. Patients in the low-risk group had a greater overall survival (OS) than those in the high-risk group. The nomogram generated based on clinical characteristics and risk scores showed strong prognostic prediction ability. The NFRG signature was an independent prognostic predictor for GBM. The low-risk group was more likely to benefit from immunotherapy based on the degree of immune cell infiltration, expression of immune checkpoints (ICs), and predicted response to immunotherapy. In the end, 2 NFRGs (EN1 and LOXL1) were identified as crucial for the development of Parkinson’s disease and the outcome of GBM.ConclusionsOur study revealed that 4 NFRGs are involved in the progression of PD. The 7-NFRGs risk score model can predict the prognosis of GBM patients and help clinicians to classify the GBM patients into high and low risk groups. EN1, and LOXL1 can be used as therapeutic targets for personalized immunotherapy for patients with PD and GBM.

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Section: Discussionmentioning

confidence: 99%

Identification and validation of neurotrophic factor-related gene signatures in glioblastoma and Parkinson’s disease

et al. 2023

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“…In addition, paracrine/autocrine loops involving MMP-9 have been suggested to amplify microglia activation, whereas deletion of MMP-9 maintained microglia in a resting phenotype in an animal model of spinal cord injury ( 78 ). These findings suggest a broader functional spectrum of MMP-9 and other matrix metalloproteinases (MMPs) released by microglia beyond established physiological roles in synaptic plasticity and extracellular matrix modeling ( 79 ) or pathological roles in neuroinflammation or gliomas, for example ( 77 , 80 , 81 ).…”

Section: Discussionmentioning

confidence: 99%

Microglia subtypes show substrate- and time-dependent phagocytosis preferences and phenotype plasticity

Wernersbach

Harms

et al. 2022

Front. Immunol.

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Microglia are phagocytosis-competent CNS cells comprising a spectrum of subtypes with beneficial and/or detrimental functions in acute and chronic neurodegenerative disorders. The heterogeneity of microglia suggests differences in phagocytic activity and phenotype plasticity between microglia subtypes. To study these issues, primary murine glial cultures were cultivated in the presence of serum, different growth factors and cytokines to obtain M0-like, M1-like, and M2-like microglia as confirmed by morphology, M1/M2 gene marker expression, and nitric oxide assay. Single-cell analysis after 3 hours of phagocytosis of E.coli particles or IgG-opsonized beads showed equal internalization by M0-like microglia, whereas M1-like microglia preferably internalized E.coli particles and M2-like microglia preferably internalized IgG beads, suggesting subtype-specific preferences for different phagocytosis substrates. Time-lapse live-cells imaging over 16 hours revealed further differences between microglia subtypes in phagocytosis preference and internalization dynamics. M0- and, more efficiently, M1-like microglia continuously internalized E.coli particles for 16 hours, whereas M2-like microglia discontinued internalization after approximately 8 hours. IgG beads were continuously internalized by M0- and M1-like microglia but strikingly less by M2-like microglia. M2-like microglia initially showed continuous internalization similar to M0-like microglia but again discontinuation of internalization after 8 hours suggesting that the time of substrate exposure differently affect microglia subtypes. After prolonged exposure to E.coli particles or IgG beads for 5 days all microglia subtypes showed increased internalization of E.coli particles compared to IgG beads, increased nitric oxide release and up-regulation of M1 gene markers, irrespectively of the phagocytosis substrate, suggesting phenotype plasticity. In summary, microglia subtypes show substrate- and time-dependent phagocytosis preferences and phenotype plasticity. The results suggest that prolonged phagocytosis substrate exposure enhances M1-like profiles and M2-M1 repolarization of microglia. Similar processes may also take place in conditions of acute and chronic brain insults when microglia encounter different types of phagocytic substrates.

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“…Interestingly, the authors further demonstrated that GBM-interacting microglia show up-regulated expression of phagocytic receptors ( Cd93 , Msr1 , Cd36 , Olr1 , Megf10 , Clec7a , Scarf1 ) and extracellular matrix (ECM) degrading enzymes such as Mmp14 [ 103 ]. A recent study supports the invasion-facilitating role of microglial cells by describing that glial cell line-derived neurotrophic factor (GDNF), a chemoattractant of microglia [ 105 ], stimulates the production of microglia-derived MMP9 and MMP14 in neonatal mice [ 106 ]. Huang et al further indicated that GDNF induced up-regulation of microglial TLR1 and TLR2 and that the activation of TLR2 can increase expression of microglial MMP9 and MMP14 [ 106 ].…”

Section: Glioblastoma Weakens Microglia/macrophage Defence Mechanismsmentioning

confidence: 99%

“…A recent study supports the invasion-facilitating role of microglial cells by describing that glial cell line-derived neurotrophic factor (GDNF), a chemoattractant of microglia [ 105 ], stimulates the production of microglia-derived MMP9 and MMP14 in neonatal mice [ 106 ]. Huang et al further indicated that GDNF induced up-regulation of microglial TLR1 and TLR2 and that the activation of TLR2 can increase expression of microglial MMP9 and MMP14 [ 106 ]. In addition to stimulating expression of ECM degrading enzymes, the activation of TLR2 also inhibited expression of MHC class II by microglial cells via loss of histone H3 acetylation at the master regulator of MHC class II molecule transcription, Ciita (Class II Major Histocompatibility Complex Transactivator).…”

Section: Glioblastoma Weakens Microglia/macrophage Defence Mechanismsmentioning

confidence: 99%

Microglia and Brain Macrophages as Drivers of Glioma Progression

Zheng

Graeber

2022

IJMS

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Evidence is accumulating that the tumour microenvironment (TME) has a key role in the progression of gliomas. Non-neoplastic cells in addition to the tumour cells are therefore finding increasing attention. Microglia and other glioma-associated macrophages are at the centre of this interest especially in the context of therapeutic considerations. New ideas have emerged regarding the role of microglia and, more recently, blood-derived brain macrophages in glioblastoma (GBM) progression. We are now beginning to understand the mechanisms that allow malignant glioma cells to weaken microglia and brain macrophage defence mechanisms. Surface molecules and cytokines have a prominent role in microglia/macrophage-glioma cell interactions, and we discuss them in detail. The involvement of exosomes and microRNAs forms another focus of this review. In addition, certain microglia and glioma cell pathways deserve special attention. These “synergistic” (we suggest calling them “Janus”) pathways are active in both glioma cells and microglia/macrophages where they act in concert supporting malignant glioma progression. Examples include CCN4 (WISP1)/Integrin α6β1/Akt and CHI3L1/PI3K/Akt/mTOR. They represent attractive therapeutic targets.

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Glial cell line‐derived neurotrophic factor increases matrix metallopeptidase 9 and 14 expression in microglia and promotes microglia‐mediated glioma progression

Cited by 13 publications

References 31 publications

Identification and validation of neurotrophic factor-related gene signatures in glioblastoma and Parkinson’s disease

Identification and validation of neurotrophic factor-related gene signatures in glioblastoma and Parkinson’s disease

Microglia subtypes show substrate- and time-dependent phagocytosis preferences and phenotype plasticity

Microglia and Brain Macrophages as Drivers of Glioma Progression

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