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Astrocyte-targeted gene delivery of interleukin 2 specifically increases brain-resident regulatory T cell numbers and protects against pathological neuroinflammation

ABSTRACT: Astrocyte-targeted gene delivery of interleukin 2 specifically increases brain-resident regulatory T cell numbers and protects against pathological neuroinflammation

PROVIDER: PRJNA742653 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14999746_1.fastq.gz	Fastqsanger.gz
	SRR14999746_2.fastq.gz	Fastqsanger.gz
	SRR14999747_1.fastq.gz	Fastqsanger.gz
	SRR14999747_2.fastq.gz	Fastqsanger.gz
	SRR14999748_1.fastq.gz	Fastqsanger.gz

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Astrocyte-targeted gene delivery of interleukin 2 specifically increases brain-resident regulatory T cell numbers and protects against pathological neuroinflammation

Project description:Astrocyte-targeted gene delivery of interleukin 2 specifically increases brain-resident regulatory T cell numbers and protects against pathological neuroinflammation

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Astrocyte-targeted gene delivery of interleukin 2 specifically increases brain-resident regulatory T cell numbers and protects against pathological neuroinflammation

Project description:The ability of immune-modulating biologics to prevent and reverse pathology has transformed recent clinical practice. Full utility in the neuroinflammation space, however, requires identification of both effective targets for local immune-modulation and a delivery system capable of crossing the blood-brain-barrier. The recent identification and characterization of a small population of regulatory T (Treg) cells resident in the brain presents one such potential therapeutic target. Here we identified brain interleukin 2 (IL-2) levels as a limiting factor for brain-resident Treg cells. We developed a gene-delivery approach for astrocytes, with a small-molecule on-switch to allow temporal control, and enhanced production in reactive astrocytes to spatially direct delivery to inflammatory sites. Mice with brain-specific IL-2 delivery were protected from traumatic brain injury, stroke and multiple sclerosis models, without impacting the peripheral immune system. These results validate brain-specific IL-2 gene delivery as effective protection against neuroinflammation, and provide a versatile platform for delivery of diverse biologics to neuroinflammatory patients.

2022-03-21 | GSE153427 | GEO

Astrocyte-targeted gene delivery of interleukin 2 specifically increases brain-resident regulatory T cell numbers and protects against pathological neuroinflammation

2022-03-21 | GSE179176 | GEO

Astrocyte-targeted gene delivery of interleukin 2 specifically increases brain-resident regulatory T cell numbers and protects against pathological neuroinflammation.

Project description:The ability of immune-modulating biologics to prevent and reverse pathology has transformed recent clinical practice. Full utility in the neuroinflammation space, however, requires identification of both effective targets for local immune modulation and a delivery system capable of crossing the blood-brain barrier. The recent identification and characterization of a small population of regulatory T (Treg) cells resident in the brain presents one such potential therapeutic target. Here, we identified brain interleukin 2 (IL-2) levels as a limiting factor for brain-resident Treg cells. We developed a gene-delivery approach for astrocytes, with a small-molecule on-switch to allow temporal control, and enhanced production in reactive astrocytes to spatially direct delivery to inflammatory sites. Mice with brain-specific IL-2 delivery were protected in traumatic brain injury, stroke and multiple sclerosis models, without impacting the peripheral immune system. These results validate brain-specific IL-2 gene delivery as effective protection against neuroinflammation, and provide a versatile platform for delivery of diverse biologics to neuroinflammatory patients.

| S-EPMC9174055 | biostudies-literature

Human astrocyte encapsulation for delivery of cytokines to modulate neuroinflammation

Project description:Human astrocyte encapsulation for delivery of cytokines to modulate neuroinflammation

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Microglia-specific IL-10 gene delivery inhibits neuroinflammation and neurodegeneration in a mouse model of Parkinson’s disease

Project description:Neuroinflammation plays a key role in modulating dopaminergic neuronal (DAN) cell loss in Parkinson’s disease (PD). However, it remains unresolved how to effectively normalize this immune response given the complex interplay between the innate and adaptive immune responses occurring within a scarcely accessible organ like the brain. In this study, we uncovered a consistent correlation between neuroinflammation, brain parenchymal lymphocytes and DAN cell loss among several commonly used mouse models of PD generated by a variety of pathological triggers. We validated a viral therapeutic approach for the microglia-specific expression of Interleukin 10 (IL-10) to selectively mitigate the excessive inflammatory response. We found that this approach induced a local nigral IL-10 release that sustained a robust neuroprotection against α-Synuclein (αSYN)-induced neurodegeneration. Single-cell transcriptomics revealed the emergence of a molecularly alternative microglial cell state specifically induced by IL-10 enriched in markers of cell activation with enhanced expression of prophagocytic pathways. Indeed, Il-10 strongly promoted phagocytotic and clearance activities that effectively reduced the αSYN aggregate burden in the nigral area. Furthermore, IL-10 stimulated the differentiation of CD4+ T lymphocytes into active T regulatory cells. Finally, CD8+ T cells exhibited enhanced inhibitory characteristics in the presence of IL-10. Thus, IL-10 local transduction elicited a strong immunomodulation in the nigral tissue with enhanced suppression of lymphocyte toxicity, which rescued DAN cell loss. These results offer insights into the therapeutic benefits induced by IL-10, showcasing a promising gene delivery approach that minimizes undesired side effects and has a strong translational relevance.

2024-07-03 | GSE225832 | GEO

Astrocyte alterations that accompany neuroinflammation induced anhedonia

Project description:Astrocyte alterations that accompany neuroinflammation induced anhedonia

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Gene expression changes in LPS-induced neuroinflammation

Project description:Neuroinflammation plays a role in the progression of several neurodegenerative disorders. We used a lipolysaccharide (LPS) model of neuroinflammation to characterize the gene expression changes underlying the inflammatory and behavioral effects of neuroinflammation. A single intracerebroventricular injection of LPS (5 ug) was administered into the lateral ventricle of mice and, 24 hours later, we examined gene expression in the cerebral cortex and hippocampus using microarray technology. Gene Ontology (GO) terms for inflammation and the ribosome were significantly enriched by LPS, whereas GO terms associated with learning and memory had decreased expression. We detected 224 changed transcripts in the cerebral cortex and 170 in the hippocampus. Expression of Egr1 (also known as Zif268) and Arc, two genes associated with learning and memory, was significantly lower in the cortex, but not hippocampus, of LPS-treated animals. Overall, altered expression of these genes may underlie some of the inflammatory and behavioral effects of neuroinflammation. Mice were given intracerebroventricular injections of saline vehicle (n = 4) or lipopolysaccharide (n = 4). Twenty-four hours later, we dissected the hippocampus and cerebral cortex and processed the tissue for microarray analysis. Gene expression changes observed in the microaray data were validated with quantitative real-time PCR.

2008-11-01 | E-GEOD-12284 | biostudies-arrayexpress

Human astrocyte encapsulation for delivery of cytokines to modulate neuroinflammation

Project description:RNAsequencing for comparison of human pluripotent stem cell-derived astrocyte response to inflammatory cytokine treatment (Interleukin 1 alpha, TNFalpha, and Complement C1q; aka ITC) while encapsulated within alginate capsules (aka AstroCapsules).

2024-12-31 | GSE275189 | GEO

Transcriptional profiling in microglia and peripheral macrophages phenotypes during development and neuroinflammation in mouse

Project description:Understanding the respective role of microglia and infiltrating monocytes in neuroinflammatory conditions has recently seemed possible by the identification of a specific microglia signature. Here instead we provide evidence that peripheral macrophages may express some of the most commonly described microglia markers at some developmental stages or pathological conditions, in particular during chronic neuroinflammation. Further, our data support the hypothesis about phenotypic plasticity and convergence among distinct myeloid cells so that they may act as a functional unit rather than as different entities, boosting their mutual functions in different phases of disease. This holds relevant implications in the view of the growing use of myeloid cell therapies to treat brain disease in humans.

2020-10-12 | E-MTAB-8059 | biostudies-arrayexpress

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