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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: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE179176 | GEO | 2022/03/21

REPOSITORIES: GEO

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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

Synthetic expansion of brain regulatory T cells effectively prevents neuroinflammatory disease II

Project description:An adaptive immunological component to neuroinflammatory diseases is increasingly being recognized. The recent identification and characterization of a small population of regulatory T cells (Tregs) resident in the brain allows for the potential therapeutic exploitation. As the most potent known anti-inflammatory mediators, Tregs have the capacity to reduce inflammation and promote tissue repair, with a key limitation being the small number present in brain tissue. Here we demonstrate that transgenic ‘micro-dosing’ of IL-2 production to the brain allows the efficient expansion of the brain-resident Treg population. This approach, using expression of IL-2 within the normal physiological range but redirected to the brain, allows a 10-fold accumulation of Treg numbers within the brain without any increase in the Treg numbers in circulating or peripheral tissues. No alteration was observed in the frequency or transcriptional profile of non-Treg populations within the brain, and, apart from the numerical expansion, brain-resident Tregs were unaltered in their transcriptional profile. Mice with expanded brain-resident Treg numbers were protected from neuroinflammation and damage in mouse models of traumatic brain injury, stroke and Multiple Sclerosis, with substantial reductions in inflammation and histological damage, and improvements in clinical measurements. To produce a treatment with translational potential, we engineered a viral vector delivery system, capable of specific production of IL-2 in the brain. This treatment approach provided a titratable expansion of brain Tregs, and effective protection against neuroinflammatory disease, with potential translation to the patient context.

2022-06-10 | GSE156935 | GEO

Interleukin-3 coordinates glial-peripheral immune crosstalk to incite multiple sclerosis

Project description:Multiple sclerosis (MS) is a neuroinflammatory disease of the central nervous system (CNS). While CNS-resident glial cells and infiltrating immune cells contribute to MS pathogenesis, the networks that govern peripheral-central immune crosstalk and coordinate functionality among these ontologically distinct populations remain unclear. Here we show, in mice and humans, that astrocyte- and CD44hiCD4+ T cell-sourced interleukin-3 (IL-3) programs microglia and infiltrating myeloid cells to exacerbate neuroinflammation by inciting a cellular recruitment program that drives the accrual of immune cells in the CNS thereby worsening MS and its preclinical model experimental autoimmune encephalomyelitis (EAE). We find that CNS-resident astrocytes and peripherally-derived CD44hiCD4+ T cells generate IL-3 while resident microglia and infiltrating monocytes, macrophages, and dendritic cells respond to the cytokine by expressing IL-3Rɑ, IL-3's specific receptor. Astrocytic and T cell IL-3 elicit an immune migratory, recruitment, and chemotactic program by IL-3Rɑ+ myeloid cells that enhances immune cell infiltration into the CNS leading to exacerbated neuroinflammation, demyelination, and clinical disease. Multiregional single-nuclei RNA sequencing (snRNAseq) of human CNS tissue from unaffected controls and MS patients reveals the appearance of a subset of IL3RA-expressing myeloid cells in MS plaques with unique recruitment, migratory, and chemotactic programing and function. In humans with MS, IL3RA expression by plaque myeloid cells and IL-3 levels in the cerebrospinal fluid (CSF) predict myeloid and T cell abundance and recruitment into the CNS. Together, our findings establish IL-3:IL-3RA signaling as a bidirectional glial-peripheral immune crosstalk network that promotes neuroinflammation, prompts immune cell recruitment to the CNS, and worsens MS.

2023-05-16 | GSE227781 | GEO

Autophagy receptor SHISA9 orchestrates antiviral immune heterogeneity of brain glia cells and CNS inflammation

Project description:Brain glia cells exhibit highly heterogeneity which can modify their genetic landscape and responding sensitivity, thus achieving appropriate responses to environmental changes for maintenance of CNS homeostasis. However, technical restriction has prevented the study on the self-orchestrating activity of CNS resident immune cells. Microglia and astrocytes are predominant responding cells at early stages during CNS viral infection. Their activation not only contributes to the recruitment of peripheral immune cells that aid in viral clearance, but also increases the risk of long-term detrimental inflammatory injury associated with many neurodegenerative diseases. Optimal autophagic activity is vital to maintain brain integrity, yet the autophagy regulation of immune activity in brain glia cells remains poorly understood. Here, we identify the membrane protein SHISA9 as an autophagy cargo receptor that modulates the heterogenic immune responses during CNS infection. By 10x single-cell RNA sequencing, we identify the astrocytes with increased Shisa9 expression followed by decreased expression of inflammatory transcriptional programs. Shisa9 has temporal characteristics in modulating both antiviral and inflammatory responses in microglia and astrocytes at different stages during infection. Shisa9-/- mice are highly susceptible to herpes simplex virus encephalitis, accompanied by higher rates of pathogenic astrocytes which might contribute to neurodegeneration progression and display a more severe neuroinflammation symptoms compared to wild-type mice. Taken together, our study unravels a critical role of selective autophagy in orchestrating immune heterogeneity of different CNS resident cells through SHISA9-IKKi axis.

2023-01-15 | GSE216271 | GEO

Human induced pluripotent stem cell-derived astrocytes are differentially activated by multiple sclerosis-associated cytokines

Project description:Recent studies highlighted the importance of astrocytes in neuroinflammatory diseases, interacting closely with other CNS cells but also with the immune system. However, due to the difficulty in obtaining human astrocytes, their role in these pathologies is still poorly characterized. Here, we develop a new serum-free protocol to differentiate human iPSCs into astrocytes. Gene expression and functional assays show that our protocol consistently yields a highly enriched population of resting mature astrocytes across the thirteen hiPSC lines differentiated. Using this new model, we first highlight the importance of serum-free media for astrocyte culture to generate resting astrocytes. Second, we assess the astrocytic response to IL-1β, TNFα and IL-6, all cytokines important in neuroinflammation, such as multiple sclerosis. Our study reveals very specific profiles of reactive astrocytes depending on the triggering stimulus. This new model provides ideal conditions for in-depth and unbiased characterization of astrocyte reactivity in neuroinflammatory conditions.

2018-11-01 | GSE120411 | GEO

Ndfip1 restricts mTORC1 signalling and glycolysis in regulatory T cells to prevent autoinflammatory disease

Project description:Project abstract: Foxp3+ T regulatory (Treg) cells have important functions in suppressing immune cell activation and establishing normal immune homeostasis. How Treg cells maintain their identity is not completely understood. Here we show that Ndfip1, a co-activator of Nedd4-family E3 ubiquitin ligases, is required for Treg cell stability and function. Ndfip1 deletion in Treg cells disrupts immune homeostasis and results in autoinflammatory disease. Ndfip1-deficient Treg cells are highly proliferative and are more likely to lose Foxp3 expression to become IL-4-producing TH2 effector cells. Proteomic analyses indicate that Ndfip1 deficiency alters the metabolic signature of Treg cells. Metabolic profiling reveals elevated glycolysis and increased mTORC1 signalling. Additional data suggest that Ndfip1 restricts Treg cell metabolic capacity and IL-4 production via distinct mechanisms. Thus, Ndfip1 preserves Treg lineage stability by preventing the expansion of highly proliferative and metabolically active cells that can cause immunopathology via secretion of IL-4.

2017-04-19 | PXD006251 | Pride

Embryonic stem cell-derived brainstem and spinal astrocyte-like cells develop a neurotoxic phenotype in vitro following clinically relevant pro-inflammatory stimulation

Project description:Traumatic axonal injury (TAI) in the brainstem carries a particularly poor prognosis. Although the role of neuroinflammation in this process is incompletely characterized, astrogliosis has been shown to coincide with TAI. Moreover, astrogliotic forebrain astrocytes were recently shown to confer a toxic effect on neurons. We sought to assess if ventral brainstem- or rostroventral spinal astrocytes exert similar effects on motor neurons in vitro. We derived brainstem/rostroventral spinal astrocyte-like cells (ES-astrocytes) and motor neurons using directed differentiation of embryonic stem cells (ES). ES-astrocyte identity was assessed using RNA-sequencing, immunocytochemistry, and comparison with primary subventricular zone-astrocytes. We activated the ES-astrocytes using the neurotoxicity-eliciting cytokines interleukin- (IL-) 1α and tumor necrosis factor-(TNF-)α. In co-cultures with reactive ES-astrocytes and motor neurons, we demonstrated neurotoxic ES-astrocyte activity, similarly to what has previously been shown for other central nervous system (CNS) regions. When exposed to IL-1β and IL-6, two neuroinflammatory cytokines found in the cerebrospinal fluid and serum proteome following severe traumatic brain injury (TBI), ES-astrocytes exerted similar effects on motor neurons. This demonstrates that ventral brainstem and rostroventral spinal cord astrocytes can exert neurotoxic effects in vitro. This highlights the importance of neuroinflammation as a secondary injury mechanism following neurotrauma, and presents a possible treatment avenue to improve neuronal survival in particularly vulnerable CNS regions following TAI.

2023-04-02 | GSE213804 | GEO

Distinct roles for IL-27 and IFN-g in the development of T-bet+ Treg required to limit infection-induced pathology

Project description:IL-27 is a potent antagonist of TH1-mediated inflammation, but the basis for this effect is not fully understood. Recent studies identified a population of T-bet+ CXCR3+ Treg that limit TH1-mediated immune pathology. The studies presented here demonstrate that IL-27-mediated STAT1 activation promotes Treg expression of T-bet and CXCR3. Infection with Toxoplasma gondii induced a similar Treg population that limits T cell responses and this population at mucosal sites is IL-27-dependent. Furthermore, transfer of Treg ameliorated the infection-induced CD4+ T cell-mediated pathology observed in IL-27p28-/- mice. Although IFN-γ promoted a similar population of cells in the periphery, it did not compensate for the absence of IL-27 at mucosal sites and microarray analysis revealed that Treg exposed to either cytokine have distinct transcriptional profiles. These findings suggest that IFN-γ and IL-27 have different roles in Treg biology but define IL-27 as a key cytokine that promotes the development of Treg specialized to control TH1 immunity. Three conditions were analyzed across two timepoints. Inducible regulatory T cells (iTreg) were generated in vitro in the presence of IL-27, IFNg or under 'Neutral' conditions as a control. Samples were collected at 10 hours and 2 days during the culture period. Three biological replicates were used for each condition.

2012-09-07 | E-GEOD-38686 | biostudies-arrayexpress

Peri-alloHCT IL-33 administration expands recipient T regulatory cells that protect mice against acute GvHD

Project description:Graft-versus-Host Disease (GvH) is the excessive inflammatory response by mature T cells contained in the graft during bone marrow transplantation. The allogeneic T cells recognize self-antigens as foreign and systemically attack multiple organs mostly with epithelial structures such as the skin, liver and gastrointestinal tract. We could show that IL-33 administration during allogeneic hematopoietic cell transplantation (alloHCT) increased regulatory T cell (Treg) numbers and ameliorated the outcome of GvHD. Furthermore, it is known that IL-33 also has an impact on myeloid cell compartments and we showed that IL-33 delivery together with a loss of FoxP3 positive Treg led to a massive expansion of myeloid cells. With the underlying experiment we wanted to further characterize the myeloid cells when Treg are lost, therefore mice were treated with IL-33 and one group had a loss in FoxP3 cells. CD11b+F4/80+Gr-1lo myeloid cells were sorted and analyzed in the microarray. The examined myeloid cell population shows strong activation of the IFNg transcriptome and are prone to M1 macrophage polarization. Therefore, Treg restrain myeloid cell expansion and polarization during IL-33 delivery.

2016-06-27 | E-MTAB-4677 | biostudies-arrayexpress

Transcriptional characterization of iPSC-derived microglia as a model for therapeutic development in neurodegeneration [scRNA-seq]

Project description:Microglia are the resident immune cells in the brain that play a key role in driving neuroinflammation. In this study, we performed transcriptional characterization of commercially available human iPSC-derived microglia-like (iMGL) cells by bulk and single cell RNA sequencing.

2023-02-28 | GSE226077 | GEO

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