Pro-inflammatory and proliferative microglia drive progression of glioblastoma

Liu, Hailong; Sun, Yu; Zhang, Qian; Jin, Wei; Gordon, Renata E.; Zhang, Yanyang; Wang, Jian; Sun, Chuanyu; Wang, Zeyuan John; Qi, Xueling; Zhang, Junping; Huang, Boyuan; Gui, Qiuping; Yuan, Hongyu; Chen, Ling; Ma, Xiaodong; Fang, Chuan; Liu, Yongqiang; Yu, Xinguang; Feng, Shiyu

doi:10.1016/j.celrep.2021.109718

Cited by 93 publications

(78 citation statements)

References 52 publications

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“…A recent study revealed that inflammasome response to HSV is primarily mediated by microglia and contributes to mortality independent of controlling viral replication [ 87 ]. Similar to our novel HSE-associated microglial transcriptomic findings, a novel subset of high-grade glioma-associated microglia exhibiting inflammasome-mediated pro-inflammatory and proliferative signatures has been recently described [ 88 ]. Another study reported that neurotoxic CCR9 + ACOD1 + microglia producing high levels of TNF-α was observed in the CNS of mice infected with neurotrophic pathogens.…”

Section: Discussionsupporting

confidence: 80%

Single-cell transcriptomics of the ventral posterolateral nucleus-enriched thalamic regions from HSV-1-infected mice reveal a novel microglia/microglia-like transcriptional response

Uyar

Domínguez

Bordeleau

et al. 2022

J Neuroinflammation

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Background Microglia participate in the immune response upon central nervous system (CNS) infections. However, the role of these cells during herpes simplex encephalitis (HSE) has not been fully characterized. We sought to identify different microglia/microglia-like cells and describe the potential mechanisms and signaling pathways involved during HSE. Methods The transcriptional response of CD11b+ immune cells, including microglia/microglia-like cells, was investigated using single-cell RNA sequencing (scRNA-seq) on cells isolated from the ventral posterolateral nucleus (VPL)-enriched thalamic regions of C57BL/6 N mice intranasally infected with herpes simplex virus-1 (HSV-1) (6 × 105 PFUs/20 µl). We further performed scanning electronic microscopy (SEM) analysis in VPL regions on day 6 post-infection (p.i.) to provide insight into microglial functions. Results We describe a novel microglia-like transcriptional response associated with a rare cell population (7% of all analyzed cells), named “in transition” microglia/microglia-like cells in HSE. This new microglia-like transcriptional signature, found in the highly infected thalamic regions, was enriched in specific genes (Retnlg, Cxcr2, Il1f9) usually associated with neutrophils. Pathway analysis of this cell-type transcriptome showed increased NLRP3-inflammasome-mediated interleukin IL-1β production, promoting a pro-inflammatory response. These cells' increased expression of viral transcripts suggests that the distinct “in transition” transcriptome corresponds to the intrinsic antiviral immune signaling of HSV-1-infected microglia/microglia-like cells in the thalamus. In accordance with this phenotype, we observed several TMEM119+/IBA-I+ microglia/microglia-like cells immunostained for HSV-1 in highly infected regions. Conclusions A new microglia/microglia-like state may potentially shed light on how microglia could react to HSV-1 infection. Our observations suggest that infected microglia/microglia-like cells contribute to an exacerbated CNS inflammation. Further characterization of this transitory state of the microglia/microglia-like cell transcriptome may allow the development of novel immunomodulatory approaches to improve HSE outcomes by regulating the microglial immune response.

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Section: Discussionsupporting

confidence: 80%

Single-cell transcriptomics of the ventral posterolateral nucleus-enriched thalamic regions from HSV-1-infected mice reveal a novel microglia/microglia-like transcriptional response

Uyar

Domínguez

Bordeleau

et al. 2022

J Neuroinflammation

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“…While there were no differences in IL1A expression, IL1B expression was higher in IDH-WT samples (Fig. 1A, P<0.05), consistent with a recent report showing that IL-1b increases the growth of IDH-WT tumors (Liu et al, 2021). To determine whether IL-1 and its signaling pathway impact survival of patient with IDH-WT GBM, we used a Cox Proportional Hazards regression model to assess survival as a function of the following independent covariates: (1) each of the genes associated with IL1 signaling, (2) the entire pathway (specifically, the average normalized expression of all genes of the pathway, and (3) a subset of selected genes (the average normalized expression of CASP1, IL1A, IL1B, IL1R1, IL1RAP, MYD88, TRAF6, TOLLIP, JUN, NFKB1, highlighted in Fig.…”

Section: Resultssupporting

confidence: 91%

A paracrine circuit of IL-1β/IL-1R1 between myeloid and tumor cells drives glioblastoma progression

Chen

Giotti

Kaluzová

et al. 2022

Preprint

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Monocytes and monocyte-derived macrophages (MDM) from blood circulation infiltrate and promote glioblastoma growth. Here we discover that glioma cells induce the expression of potent pro-inflammatory cytokine IL-1b in MDM, which engages IL-1R1 in glioma cells, activates NF-kB pathway, and subsequently leads to the induction of monocyte chemoattractant proteins (MCPs). Thus, a feedforward paracrine circuit of IL-b/IL-1R1 between the tumors and MDM creates an interdependence driving glioblastoma progression. Locally antagonizing IL-1b/IL-1R1 leads to reduced MDM infiltration, diminished tumor growth, reduced exhausted CD8+ T cells, and thereby extends the survival of tumor-bearing mice. In contrast to IL-1b, IL-1a exhibits anti-tumor effects. Genetic deletion of Il1a is associated with decreased recruitment of lymphoid cells and loss of interferon (IFN) signaling in various immune populations and subsets of malignant cells. Local antagonism of IL-1b should be considered as an effective anti-glioblastoma therapy.

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“…Therefore, to assess a local neuroinflammatory response specific for microglia, we have also measured by western blot the expression of the microglial-specific marker TMEM119 in the brain tissue of the rats at different time-points of pneumococcal meningitis. it was recently described that TMEM119 is downregulated in microglia during neuroinflammation and brain disease [15][16][17][18][19]. In line with what reported in literature, we observed a consistent decrease of TMEM119 expression in brain homogenates from 4 up to 72 hours of pneumococcal infection (Figures 6A and 6C).…”

Section: Increased Neuroinflammation Neuronal Cell Damage and Impaire...supporting

confidence: 92%

Dysfunctional glymphatic system with disrupted aquaporin-4 expression pattern on astrocytes causes bacterial product accumulation in the CSF during pneumococcal meningitis

Generoso

Thorsdottir

Collodel

et al. 2022

Preprint

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BACKGROUND: Pneumococcal meningitis, inflammation of the meninges due to an infection of the Central Nervous System caused by Streptococcus pneumoniae (the pneumococcus), is the most common form of community-acquired bacterial meningitis globally. The brain is separated from the systemic circulation by the blood-brain barrier (BBB), and meningitis triggers the host immune response increasing the BBB permeability, allowing peripheral immune cells to reach the cerebrospinal fluid (CSF), and increasing debris production. The glymphatic system is a glial-dependent clearance pathway that drives the exchange of compounds between the brain parenchyma and the CSF regulating the waste clearance away from the brain. Aquaporin-4 (AQP4)-water channels on astrocytic end feet regulate the solute transport of the glymphatic system. METHODS AND RESULTS: Wistar rats, either subjected to pneumococcal meningitis or to artificial-CSF (sham), received Evans blue albumin (EBA) intracisternal. Overall, the meningitis group presented a significant impairment of the glymphatic system by retaining the EBA in the brain without consistently releasing the EBA into the bloodstream compared to the sham non-infected group. Through western blot and immunofluorescence microscopy analysis using rat CSF and brain tissue sections, an increased accumulation of pneumococci was detected over time in the CSF, and because of a loss of drainage between CSF and brain interstitial space, such bacterial accumulation was not observed in the brain parenchyma. Western blot analysis for Iba1, TMEM119 and IFN-Ɣ in rat brain homogenates and NSE in serum showed increased neuroinflammation and neuronal damage in the brain over time during pneumococcal infection. Neurological impairment upon neuronal cell damage caused by meningitis with a malfunctioning glymphatic system was also demonstrated through open-field behavioral tests comparing rats from sham and meningitis groups. Lastly, protein expression analysis of AQP4 revealed no differences in AQP4 between the brains of the rats from the meningitis group and those from the sham non-infected rats. Importantly, confocal microscopy analysis showed a detachment of the astrocytic end feet from the BBB vascular endothelium with consequent misplacement of AQP4-water channels. CONCLUSIONS: These findings clearly indicate that pneumococcal meningitis decreases the glymphatic system's functionality, increasing the neurotoxic waste debris in the brain ultimately leading to brain-wide neuroinflammation and neuronal damage. Finally, our results clearly showed that during pneumococcal meningitis, the glymphatic system does not function because of a detachment of the astrocytic end feet from the BBB vascular endothelium, which leads to a misplacement of AQP4 with consequent the loss of the AQP4-water channel's functionality.

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Pro-inflammatory and proliferative microglia drive progression of glioblastoma

Abstract: Highlights d A subset of high-grade glioma-associated microglia (HGG-AM) is identified by scRNA-seq d TGF-b1 activated from SETD2-mut/IDH-WT GBM cells promotes activation of HGG-AM d HGG-AM exhibits pro-inflammation and proliferation features, promoting tumor progression

Cited by 93 publications

References 52 publications

Single-cell transcriptomics of the ventral posterolateral nucleus-enriched thalamic regions from HSV-1-infected mice reveal a novel microglia/microglia-like transcriptional response

Single-cell transcriptomics of the ventral posterolateral nucleus-enriched thalamic regions from HSV-1-infected mice reveal a novel microglia/microglia-like transcriptional response

A paracrine circuit of IL-1β/IL-1R1 between myeloid and tumor cells drives glioblastoma progression

Dysfunctional glymphatic system with disrupted aquaporin-4 expression pattern on astrocytes causes bacterial product accumulation in the CSF during pneumococcal meningitis

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