Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

T cell - DAM feedback loop drives CNS inflammation and neurodegenration in SPG15 at an early age via CCR5-CCL5 interaction [CD3+]

ABSTRACT: The immune system is an emerging cause of neuroinflammation and is suspected to be involved in neurodegeneration. The role of microglia, the macrophages of the Central Nervous System (CNS), was extensively researched in CNS neuropathologies. However, we only start to understand the role of T cells in diseases like Alzheimer’s Disease (AD) and Huntington’s Disease (HD) and how microglial – T cell crosstalk contributes to these pathologies. Here we tackle these topics in a rare and less investigated disease called Spastic Paraplegia 15 (SPG15) using a Zfyve26-/- mouse model. We were able to show, that CD8+ T cells and microglia potentiate a pro-inflammatory response through bidirectional communication in SPG15 KO and not WT mouse brains. The increase of CD8+ T cells in SPG15 KO animals also required a TCR dependent component. These findings are in line with previous reports on neurodegenerative disease which hints at cross-condition mechanisms involved in CD8+T cell responses in CNS, when encountering accumulation of non-degradable material in the brain.

ORGANISM(S): Mus musculus

PROVIDER: GSE244474 | GEO | 2025/04/04

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

T cell - DAM feedback loop drives CNS inflammation and neurodegenration in SPG15 at an early age [CD45+]

Project description:The immune system is an emerging cause of neuroinflammation and is suspected to be involved in neurodegeneration. The role of microglia, the macrophages of the Central Nervous System (CNS), was extensively researched in CNS neuropathologies. However, we only start to understand the role of T cells in diseases like Alzheimer’s Disease (AD) and Huntington’s Disease (HD) and how microglial – T cell crosstalk contributes to these pathologies. Here we tackle these topics in a rare and less investigated disease called Spastic Paraplegia 15 (SPG15) using a Zfyve26-/- mouse model. We were able to show, that CD8+ T cells and microglia potentiate a pro-inflammatory response through bidirectional communication in SPG15 KO and not WT mouse brains. The increase of CD8+ T cells in SPG15 KO animals also required a TCR dependent component. These findings are in line with previous reports on neurodegenerative disease which hints at cross-condition mechanisms involved in CD8+T cell responses in CNS, when encountering accumulation of non-degradable material in the brain.

2025-04-04 | GSE244476 | GEO

Therapeutic potential of human microglial transplantation in a chimeric model of CSF1R-related leukoencephalopathy

Project description:Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare, autosomal dominant primary microgliopathy caused by mutations in colony-stimulating factor 1 receptor (CSF1R). CSF1R signaling is necessary for microglial differentiation and survival. As a result, ALSP patient brains have fewer microglia and exhibit an array of neuropathologies including axonal spheroids, white matter abnormalities, reactive astrocytosis, and brain calcification. To explore the therapeutic potential of transplanting healthy human microglia, we generated ‘hFIRE’ mice, a xenotolerant mouse model of ALSP that lacks murine microglia. Remarkably, transplantation of induced pluripotent stem cell (iPSC)-derived microglial progenitors enabled rapid CNS-wide microglial engraftment, restoring a homeostatic microglial gene signature and preventing diverse ALSP-related neuropathologies. To further examine a potential autologous approach, ALSP-patient derived iPSCs were CRISPR-corrected, rescuing mutation-induced deficits in microglial proliferation, enabling brain-wide microglial engraftment, and reducing pre-existing spheroid, astroglial, and calcification pathologies within just 6 weeks. Together with the accompanying study by Munro and Colleagues, these results demonstrate the utility of FIRE mice to model diverse ALSP neuropathologies and provide initial evidence that iPSC-microglia could be further developed as a promising new therapeutic strategy for ALSP and perhaps other microglia-associated neurological disorders.

2024-04-24 | GSE253623 | GEO

Data in support of Absence of miRNA-146a differentially alters microglia function and proteome

Project description:MiR-146a is an important regulator of innate inflammatory responses and is also implicated in cell death and survival. Here, we identified microglia as the main cellular source of miR-146a among mouse CNS resident cells. We further characterized the phenotype of miR-146a KO microglia cells during in vivo demyelination induced by cuprizone (CPZ) and found reduced number of CD11c+ microglia in the KO compared to WT mice. Microglia were also isolated from the brain, and the proteome was analyzed by liquid chromatography mass spectrometry.

2020-06-29 | PXD015939 | Pride

Microglia-derived TGF-β1 ligand maintains microglia homeostasis via autocrine mechanism and is critical for normal cognitive function in adult mouse brain

Project description:While TGF-β signaling is essential for microglial function, the cellular source of TGF-β ligand and its spatial regulation remains unclear in adult CNS. Our data supports that microglia but not astrocytes or neurons are the primary producers of TGF-β1 ligands needed for microglial homeostasis. Microglia-Tgfb1 KO leads to activation of microglia featuring a dyshomeostatic transcriptomic profile that resembles disease-associated microglia (DAMs), injury-associated microglia, and aged microglia, suggesting that microglial self-produced TGF-β1 ligands are important in the adult CNS. Interestingly, astrocytes in the MG-tgfb1 iKO mice show a transcriptome profile that is closely aligned with A1-like astrocytes. Additionally, using sparse mosaic single cell microglia KO of TGF-β1 ligand we established an autocrine mechanism for TGF-β signaling. Importantly MG-Tgfb1 inducible KO mice show cognitive deficits, supporting that precise spatial regulation of TGF-β1 ligand derived from microglia is critical for the maintenance of brain homeostasis and normal cognitive function in the adult brain.

2023-08-08 | GSE236032 | GEO

The CCL5/CCR5 Axis in Cancer Progression.

Project description:Tumor cells can "hijack" chemokine networks to support tumor progression. In this context, the C-C chemokine ligand 5/C-C chemokine receptor type 5 (CCL5/CCR5) axis is gaining increasing attention, since abnormal expression and activity of CCL5 and its receptor CCR5 have been found in hematological malignancies and solid tumors. Numerous preclinical in vitro and in vivo studies have shown a key role of the CCL5/CCR5 axis in cancer, and thus provided the rationale for clinical trials using the repurposed drug maraviroc, a CCR5 antagonist used to treat HIV/AIDS. This review summarizes current knowledge on the role of the CCL5/CCR5 axis in cancer. First, it describes the involvement of the CCL5/CCR5 axis in cancer progression, including autocrine and paracrine tumor growth, ECM (extracellular matrix) remodeling and migration, cancer stem cell expansion, DNA damage repair, metabolic reprogramming, and angiogenesis. Then, it focuses on individual hematological and solid tumors in which CCL5 and CCR5 have been studied preclinically. Finally, it discusses clinical trials of strategies to counteract the CCL5/CCR5 axis in different cancers using maraviroc or therapeutic monoclonal antibodies.

| S-EPMC7407580 | biostudies-literature

Transcriptional regulation of microglia priming by IRF7, IRF9 and SMAD3 in accelerated aging mice [RNA-seq]

Project description:Microglia are the tissue resident macrophages of the central nervous system (CNS). Dysregulation of inflammatory processes in the CNS is associated with aging, and neurodegenerative diseases, where microglia acquire a sensitized, or primed, phenotype, which is characterized by an increased inflammatory phenotype and an exaggerated reactivity to immune challenges. Transcriptomic profiling of microglia in different neurodegenerative disease and aging mouse models identified a common, primed, gene expression signature. However, the transcriptional mechanisms that mediate microglia priming still remains unclear. In DNA repair deficient (Ercc1Δ/ko) mice, microglia acquire a profound primed phenotype and by integrating RNA-seq and ATAC-seq data of Ercc1Δ/ko microglia, we identified transcription factors IRF7, IRF9 and SMAD3 as possible core regulators of microglia priming. Our data suggest that increased IRF7/IRF9 activity and decreased SMAD3 activity might be important for microglia to acquire a primed gene signature. This study provides insight in the transcriptomic regulation of primed microglia, which are implicated in aging and neurodegenerative diseases.

2024-12-31 | GSE227606 | GEO

Transcriptional regulation of microglia priming by IRF7, IRF9 and SMAD3 in accelerated aging mice [ATAC-seq]

2024-12-31 | GSE227605 | GEO

Granzyme K+ CD8 T cells slow tauopathy progression by targeting microglia c

Project description:Neurodegenerative diseases trigger innate and adaptive immune responses that can either slow or accelerate disease progression. How immune cells contribute to such divergent disease outcomes is not entirely clear. Here, we sought to define beneficial immune pressure that emerged during development of tauopathies in mice and humans. Using mice that express mutant human tau in neurons, we observed that microglia slowed tauopathy development by controlling the spread of tau throughout the CNS and into the blood. However, over time microglia converted into distressed antigen presenting cells, acquired neuronal transcripts, and were targeted by resident CD8+ T cells. We detected clonally expanded CD8+ T cells in the CNS and draining lymph nodes of tauopathy mice that expressed granzyme K, but not traditional effector molecules (e.g., IFN, TNF, granzymes a/b/c), which was deposited onto the microglia they targeted. In fact, engagement of microglia by granzyme K expressing CD8+ T cells was a signature of tauopathy development in mice as well as humans with tau rich brain lesions linked to age, Alzheimer’s disease, or chronic traumatic encephalopathy. Deletion of CD8+ T cells in mice promoted the appearance of distressed microglia containing neuronal transcripts, markedly enhanced tau spread, and accelerated neurological decline. These data highlight a beneficial immune reaction involving microglia and granzyme K expressing CD8+ T cells that can slow tauopathy progression. Enhancement of this coordinated response offers the potential to improve outcomes in tauopathy patients.

2025-06-20 | GSE273757 | GEO

Granzyme K+ CD8 T cells slow tauopathy progression by targeting microglia b

2025-06-20 | GSE273753 | GEO

Granzyme K+ CD8 T cells slow tauopathy progression by targeting microglia a

2025-06-20 | GSE273752 | GEO