Immune checkpoint TIM-3 regulates microglia and Alzheimer’s disease [BulkRNAseq_Dataset3_4M]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA926118 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23176632_1.fastq.gz | Fastqsanger.gz | |||
| SRR23176632_2.fastq.gz | Fastqsanger.gz | |||
| SRR23176633_1.fastq.gz | Fastqsanger.gz | |||
| SRR23176633_2.fastq.gz | Fastqsanger.gz | |||
| SRR23176634_1.fastq.gz | Fastqsanger.gz |
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Project description:Microglia are the resident immune cells in the brain and have pivotal roles in neurodevelopment and neuroinflammation1,2. This study investigates the function of the immune-checkpoint molecule TIM-3 (encoded by HAVCR2) in microglia. TIM-3 was recently identified as a genetic risk factor for late-onset Alzheimer’s disease3, and it can induce T cell exhaustion4. However, its specific function in brain microglia remains unclear. We demonstrate in mouse models that TGFβ signalling induces TIM-3 expression in microglia. In turn, TIM-3 interacts with SMAD2 and TGFBR2 through its carboxy-terminal tail, which enhances TGFβ signalling by promoting TGFBR-mediated SMAD2 phosphorylation, and this process maintains microglial homeostasis. Genetic deletion of Havcr2 in microglia leads to increased phagocytic activity and a gene-expression profile consistent with the neurodegenerative microglial phenotype (MGnD), also referred to as disease-associated microglia (DAM). Furthermore, microglia-targeted deletion of Havcr2 ameliorates cognitive impairment and reduces amyloid-β pathology in 5×FAD mice (a transgenic model of Alzheimer’s disease). Single-nucleus RNA sequencing revealed a subpopulation of MGnD microglia in Havcr2-deficient 5×FAD mice characterized by increased pro-phagocytic and anti-inflammatory gene expression alongside reduced pro-inflammatory gene expression. These transcriptomic changes were corroborated by single-cell RNA sequencing data across most microglial clusters in Havcr2-deficient 5×FAD mice. Our findings reveal that TIM-3 mediates microglia homeostasis through TGFβ signalling and highlight the therapeutic potential of targeting microglial TIM-3 in Alzheimer’s disease.
2025-05-07 | GSE223423 | GEO
Project description:Microglia are the resident immune cells in the brain and have pivotal roles in neurodevelopment and neuroinflammation1,2. This study investigates the function of the immune-checkpoint molecule TIM-3 (encoded by HAVCR2) in microglia. TIM-3 was recently identified as a genetic risk factor for late-onset Alzheimer’s disease3, and it can induce T cell exhaustion4. However, its specific function in brain microglia remains unclear. We demonstrate in mouse models that TGFβ signalling induces TIM-3 expression in microglia. In turn, TIM-3 interacts with SMAD2 and TGFBR2 through its carboxy-terminal tail, which enhances TGFβ signalling by promoting TGFBR-mediated SMAD2 phosphorylation, and this process maintains microglial homeostasis. Genetic deletion of Havcr2 in microglia leads to increased phagocytic activity and a gene-expression profile consistent with the neurodegenerative microglial phenotype (MGnD), also referred to as disease-associated microglia (DAM). Furthermore, microglia-targeted deletion of Havcr2 ameliorates cognitive impairment and reduces amyloid-β pathology in 5×FAD mice (a transgenic model of Alzheimer’s disease). Single-nucleus RNA sequencing revealed a subpopulation of MGnD microglia in Havcr2-deficient 5×FAD mice characterized by increased pro-phagocytic and anti-inflammatory gene expression alongside reduced pro-inflammatory gene expression. These transcriptomic changes were corroborated by single-cell RNA sequencing data across most microglial clusters in Havcr2-deficient 5×FAD mice. Our findings reveal that TIM-3 mediates microglia homeostasis through TGFβ signalling and highlight the therapeutic potential of targeting microglial TIM-3 in Alzheimer’s disease.
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Project description:Microglia are the resident immune cells in the brain and have pivotal roles in neurodevelopment and neuroinflammation1,2. This study investigates the function of the immune-checkpoint molecule TIM-3 (encoded by HAVCR2) in microglia. TIM-3 was recently identified as a genetic risk factor for late-onset Alzheimer’s disease3, and it can induce T cell exhaustion4. However, its specific function in brain microglia remains unclear. We demonstrate in mouse models that TGFβ signalling induces TIM-3 expression in microglia. In turn, TIM-3 interacts with SMAD2 and TGFBR2 through its carboxy-terminal tail, which enhances TGFβ signalling by promoting TGFBR-mediated SMAD2 phosphorylation, and this process maintains microglial homeostasis. Genetic deletion of Havcr2 in microglia leads to increased phagocytic activity and a gene-expression profile consistent with the neurodegenerative microglial phenotype (MGnD), also referred to as disease-associated microglia (DAM). Furthermore, microglia-targeted deletion of Havcr2 ameliorates cognitive impairment and reduces amyloid-β pathology in 5×FAD mice (a transgenic model of Alzheimer’s disease). Single-nucleus RNA sequencing revealed a subpopulation of MGnD microglia in Havcr2-deficient 5×FAD mice characterized by increased pro-phagocytic and anti-inflammatory gene expression alongside reduced pro-inflammatory gene expression. These transcriptomic changes were corroborated by single-cell RNA sequencing data across most microglial clusters in Havcr2-deficient 5×FAD mice. Our findings reveal that TIM-3 mediates microglia homeostasis through TGFβ signalling and highlight the therapeutic potential of targeting microglial TIM-3 in Alzheimer’s disease.
2025-05-07 | GSE223421 | GEO
Project description:Microglia are the resident immune cells in the brain and have pivotal roles in neurodevelopment and neuroinflammation1,2. This study investigates the function of the immune-checkpoint molecule TIM-3 (encoded by HAVCR2) in microglia. TIM-3 was recently identified as a genetic risk factor for late-onset Alzheimer’s disease3, and it can induce T cell exhaustion4. However, its specific function in brain microglia remains unclear. We demonstrate in mouse models that TGFβ signalling induces TIM-3 expression in microglia. In turn, TIM-3 interacts with SMAD2 and TGFBR2 through its carboxy-terminal tail, which enhances TGFβ signalling by promoting TGFBR-mediated SMAD2 phosphorylation, and this process maintains microglial homeostasis. Genetic deletion of Havcr2 in microglia leads to increased phagocytic activity and a gene-expression profile consistent with the neurodegenerative microglial phenotype (MGnD), also referred to as disease-associated microglia (DAM). Furthermore, microglia-targeted deletion of Havcr2 ameliorates cognitive impairment and reduces amyloid-β pathology in 5×FAD mice (a transgenic model of Alzheimer’s disease). Single-nucleus RNA sequencing revealed a subpopulation of MGnD microglia in Havcr2-deficient 5×FAD mice characterized by increased pro-phagocytic and anti-inflammatory gene expression alongside reduced pro-inflammatory gene expression. These transcriptomic changes were corroborated by single-cell RNA sequencing data across most microglial clusters in Havcr2-deficient 5×FAD mice. Our findings reveal that TIM-3 mediates microglia homeostasis through TGFβ signalling and highlight the therapeutic potential of targeting microglial TIM-3 in Alzheimer’s disease.
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Project description:Immune checkpoint TIM-3 regulates microglia and Alzheimer’s disease
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Project description:Immune checkpoint TIM-3 regulates microglia and Alzheimer’s disease [BulkRNAseq_Dataset1_Batch2_7M]
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Project description:Immune checkpoint TIM-3 regulates microglia and Alzheimer’s disease [BulkRNAseq_Dataset1_Batch1_3M]
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Project description:Immune checkpoint TIM-3 regulates microglia and Alzheimer’s disease [snRNAseq_5M]
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Project description:Microglia, resident immune cells in the brain, play a critical role in neurodevelopment and neurological diseases. We investigated the role of the immune checkpoint molecule Tim-3 (Havcr2), which was recently identified as a genetic risk factor for late-onset Alzheimer’s disease (LOAD) in microglia. While Tim-3 has been shown to play an important role in inducing T cell exhaustion, it shows high and specific expression in the microglia where its role is unknown. Here we show that Tim-3 expression in microglia was induced by TGFβ signaling. Mechanistically, Tim-3 binds both Smad2 and Tgfbr2 by its C-terminus tail and enhances TGFβ signaling by promoting the phosphorylation of Smad2 by Tgfbr, thereby contributing to microglial homeostasis. Genetic deletion of Tim-3 in microglia resulted in increased phagocytic activity with a gene expression profile skewed towards neurodegenerative microglia (MGnD) phenotype, also known as disease-associated microglia (DAM). Moreover, microglia-targeted deletion of Tim-3 ameliorated AD pathology in 5xFAD mice. Single-nucleus RNA sequencing (snRNA-seq) identified a subpopulation among MGnD/DAM microglia in Havcr2-deficient 5xFAD mice, characterized by increased pro-phagocytic and anti-inflammatory gene expression together with decreased proinflammatory gene expression. Additional single-cell RNAseq confirmed these transcriptomic shifts in Havcr2-deficient 5xFAD mice in most microglial clusters. Our study shows a Tim-3-mediated regulatory mechanism of homeostatic microglia through its interaction with TGFβ signaling and the beneficial role of targeting microglial Tim-3 in AD mice. Our findings promise a potential therapeutic strategy targeting checkpoint molecule Tim-3 in currently intractable AD.
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Project description:This SuperSeries is composed of the SubSeries listed below.
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