A Novel Role for A20-Regulated CNS Endothelial ICOSL in Immune Cell Adhesion and Autoimmune Neuroinflammation
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ABSTRACT:
PROVIDER: PRJNA913897 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22811805.fastq.gz | Fastqsanger.gz | |||
| SRR22811806.fastq.gz | Fastqsanger.gz | |||
| SRR22811807.fastq.gz | Fastqsanger.gz | |||
| SRR22811808.fastq.gz | Fastqsanger.gz | |||
| SRR22811809.fastq.gz | Fastqsanger.gz |
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Project description:A20 is a ubiquitin-modifying protein that negatively regulates canonical NF-κB signaling and mutations in A20/TNFAIP3 have been associated with a variety of autoimmune diseases, including multiple sclerosis (MS). We found that deletion of A20 in central nervous system (CNS) endothelial cells (BEC) enhances experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. These mice showed increased numbers of CNS-infiltrating immune cells during neuroinflammation and in the steady state. While the integrity of the barrier was not impaired, we observed a strong activation of the endothelium in A20ΔBEC mice, with dramatically increased levels of the adhesion molecules ICAM-1 and VCAM-1. We furthermore discovered ICOSL as novel adhesion molecule expressed by A20-deficient BECs. Silencing of ICOSL in BECs ameliorated the severity of an active EAE disease in wildtype mice and significantly delayed the onset of symptom development. Furthermore, blocking of ICOSL on primary CNS-derived endothelial cells impaired the adhesion of different T cell populations to the monolayer. Taken together, we here report a novel function of A20-regulated ICOSL expressed on CNS endothelial cells during inflammation. We propose that BEC-ICOSL contributes to the firm adhesion of T cells to the barrier, promoting T cell transmigration into the CNS and eventually driving autoimmune neuroinflammation.
2023-11-03 | GSE221318 | GEO
Project description:Inducible co-stimulator (ICOS) interaction with its ligand (ICOSL) is involved in several T cell effector functions. While blockade of ICOS:ICOSL interaction in chronic graft versus host disease (GVHD) seems benefi cial, results for acute GVHD remain controversial. To further elucidate its role in acute GVHD, C57BL / 6 mice were lethally irradiated and reconstituted with allogeneic spleen cells in the absence or presence of ICOSL-blocking mAb. Mice reconstituted with allogeneic spleen cells experienced severe GVHD and died untreated within 6 M-bM-^@M-^S 9 days after transplantation. Mice treated with an anti-ICOSL mAb starting from day 3 after transplantation gained weight again and survived for at least additional 12 days, although the treatment was already stopped at day 11 after transplantation. In contrast, the anti-ICOSL treatment starting from day 0 did not prevent GVHD. The diff erence between therapeutic (day 3) and prophylactic (day 0) anti-ICOSL treatment was independent of CD25 + CD4 + regulatory T cells since their depletion did not abrogate the therapeutic eff ect of ICOSL blockade. Microarray analysis revealed IFN- M-NM-3 and chemokine up-regulation in spleen cells of prophylactically treated mice, emphasizing kinetic dependence of acute GVHD modulation via blockade of ICOS:ICOSL interaction. B6 recipients were irradiated with 10.0 Gray, administered from a 137 Cs source. Splenocytes from C3H mice were prepared as single cell suspensions in PBS, depleted of red blood cells and counted. 2 M-bM-^@M-^S 3 M-CM-^W 10^7 C3H splenocytes in a volume of 200 M-NM-<l were transplanted into B6 recipients via tail vein injection (4 mice per group per experiment) 4 M-bM-^@M-^S 6 h after irradiation. Mice in the treatment group with anti-ICOSL mAb and their respective controls, received 500 M-NM-<g mAb i. p starting at day 0 or day 3, followed by subsequent injections of 200 M-NM-<g of mAb every other day. At day 4 after transplantation RNA of spleen cells was prepared and subjected to microarray analysis. Combined RNA from allogeneic transplanted mice was hybridized onto 2 independent arrays.
2009-09-14 | E-GEOD-17995 | biostudies-arrayexpress
Project description:Microglia-expressed A20 regulates synapse formation and inhibits inflammasome-dependent neuroinflammation
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Project description:Inducible co-stimulator (ICOS) interaction with its ligand (ICOSL) is involved in several T cell effector functions. While blockade of ICOS:ICOSL interaction in chronic graft versus host disease (GVHD) seems benefi cial, results for acute GVHD remain controversial. To further elucidate its role in acute GVHD, C57BL / 6 mice were lethally irradiated and reconstituted with allogeneic spleen cells in the absence or presence of ICOSL-blocking mAb. Mice reconstituted with allogeneic spleen cells experienced severe GVHD and died untreated within 6 – 9 days after transplantation. Mice treated with an anti-ICOSL mAb starting from day 3 after transplantation gained weight again and survived for at least additional 12 days, although the treatment was already stopped at day 11 after transplantation. In contrast, the anti-ICOSL treatment starting from day 0 did not prevent GVHD. The diff erence between therapeutic (day 3) and prophylactic (day 0) anti-ICOSL treatment was independent of CD25 + CD4 + regulatory T cells since their depletion did not abrogate the therapeutic eff ect of ICOSL blockade. Microarray analysis revealed IFN- γ and chemokine up-regulation in spleen cells of prophylactically treated mice, emphasizing kinetic dependence of acute GVHD modulation via blockade of ICOS:ICOSL interaction.
2009-09-14 | GSE17995 | GEO
Project description:The goal of this study is to elucidate the role of microglial A20 in maintaining brain homeostasis, comparing fully deficient to partially deficient microglia tissue
2020-09-27 | GSE123033 | GEO
Project description:Oligodendrocyte regulation during autoimmune neuroinflammation
| PRJNA755962 | ENA
Project description:To explore the potential function of CD19+ICOSL- B-cell-subset, the whole transcriptome of sorted CD19+ICOSL+ and CD19+ICOSL- B cells was profiled by using Microarray analysis.
2022-10-29 | GSE216491 | GEO
Project description:A20 is a negative regulator of NF-κB signaling, crucial to control inflammatory responses and ensure tissue homeostasis. A20 is thought to restrict NF-κB activation both by its ubiquitin-editing activity as by non-enzymatic activities. Besides its role in NF-κB signaling, A20 also acts as a protective factor inhibiting apoptosis and necroptosis. Because of the ability of A20 to both ubiquitinate and deubiquitinate substrates and its involvement in many cellular processes, we hypothesized that deletion of A20 might generally impact on protein levels, thereby disrupting cellular processes. We performed a differential proteomics study of bone marrow derived macrophages (BMDMs) from control and myeloid-specific A20 knockout mice, both in untreated conditions and after LPS and TNF treatment, and demonstrate proteome-wide changes in protein expression upon A20 deletion. Several inflammatory proteins are up-regulated in the absence of A20, even without an inflammatory stimulus. Depending on the treatment and the time, more proteins are regulated. Together these changes may affect multiple signaling pathways disturbing tissue homeostasis and inducing (autoimmune) inflammation, as suggested by genetic studies in patients.
2018-05-15 | PXD008726 | Pride
Project description:Unique and shared cytogenetic abnormalities have been documented for marginal zone lymphomas (MZLs) arising at different sites. Recently, homozygous deletions of the chromosomal band 6q23, involving the tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20) gene, a negative regulator of NF-kappa B, were described in ocular adnexal MZL, suggesting a role for A20 as a tumor suppressor in this disease entity. Here, we investigated inactivation of A20 by DNA mutations or deletions in a panel of extranodal (EMZL), nodal (NMZL) and splenic (SMZL) MZLs. Inactivating mutations encoding truncated A20 proteins were identified in 6/32 (18.8%) MZLs, including 3/11 (27.3%) EMZLs, 2/9 (22.2%) NMZLs, and 1/12 (8.3%) SMZLs. Two additional unmutated non-splenic MZLs also showed mono- or biallelic A20 deletions by FISH and/or array-CGH. Thus, A20 loss by both somatic mutations and/or deletions represents a common genetic aberration across all MZL subtypes, which may contribute to lymphomagenesis by inducing constitutive NF-kappa B activation. Keywords: Genome variation profiling by SNP array 27 MZL samples. No technical replications.
2009-04-01 | E-GEOD-13989 | biostudies-arrayexpress
Project description:Objectives: Genetic variations in TNFAIP3 (A20) de-ubiquitinase (DUB) domain increase the risk of systemic lupus erythematosus (SLE) and rheumatoid arthritis. A20 is a negative regulator of NF-κB but the role of its DUB domain and related genetic variants remain unclear. We aimed to study the functional effects of A20 DUB-domain alterations in immune cells and understand its link to SLE pathogenesis. Methods: CRISPR/Cas9 was used to generate human U937 monocytes with A20 DUB-inactivating C103A knock-in mutation. Whole genome RNA-sequencing was used to identify differentially expressed genes between WT and C103A knock-in cells. Functional studies were performed in A20 C103A U937 cells and in immune cells from A20 C103A mice and genotyped healthy individuals with A20 DUB polymorphism rs2230926. Neutrophil extracellular trap (NET) formation was adressed ex vivo in neutrophils from A20 C103A mice and SLE-patients with rs2230926. Results: Genetic disruption of A20 DUB domain in human and murine myeoloid cells did not give rise to enhanced NF-κB signaling. Instead, cells with C103A mutation or rs2230926 polymorphism presented an upregulated expression of PADI4, an enzyme regulating protein citrullination and NET formation, two key mechanisms in autoimmune pathology. A20 C103A cells exhibited enhanced protein citrullination and extracellular trap formation, which could be suppressed by selective PAD4 inhibition. Moreover, SLE-patients with rs2230926 showed increased NETs and increased frequency of autoantibodies to citrullinated epitopes. Conclusions: We propose that genetic alterations disrupting the A20 DUB domain mediate increased susceptibility to SLE through the upregulation of PADI4 with resultant protein citrullination and extracellular trap formation.
2019-07-10 | GSE116780 | GEO