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Chronic sleep deprivation promotes experimental autoimmune uveitis through STAT1 phosphorylation, ISG15 expression and enhanced pathogenicity of macrophages

ABSTRACT: Autoimmune uveitis (AU) is a severe intraocular inflammatory disease driven by dysregulated T-cell immunity and macrophage activation, leading to retinal tissue damage. Experimental autoimmune uveitis (EAU), an animal model, closely mimics human AU, highlighting the role of macrophages in inflammation and immune regulation. Chronic sleep deprivation (CSD), caused by prolonged circadian rhythm disruption, further exacerbates immune dysfunction by activating microglia and enhancing inflammation. This study investigates the combined impact of EAU and CSD on retinal transcriptomics, focusing on immune and inflammatory pathways, providing insights into the interaction between circadian rhythm disruptions and autoimmune uveitis progression.

ORGANISM(S): Mus musculus

PROVIDER: GSE284505 | GEO | 2024/12/22

REPOSITORIES: GEO

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Single-Cell transcriptional profiling reveals immune dysregulation and abnormal immune-inflammatory communications between immune and retinal cells in uveitis

Project description:Uveitis is an immune-inflammatory disease that can cause blindness. However, little is known about a comprehensive atlas of the ocular cellular and inflammatory components in uveitis. Here, single-cell RNA sequencing was performed to construct a transcriptomic atlas of ocular cells from experimental autoimmune uveitis (EAU) and control mice to identify disease- associated immune cell subsets and molecules. We reveal 15 cell types in eyes and found an α-Synuclein positive microglia subset and plasma cell subset with high level of cytokines. The heterogeneous plasma cells subsets communicated with DC, T cells and retinal cells via various cytokines and molecular pairing. The G protein Rab1A participated in the inflammatory response of plasma cells. Altogether, we revealed the heterogeneous inflammatory genes, EAU-specific immune cell populations, and dysregulated communications of immune and retinal cells in EAU. This result provides a systematic view of the transcriptional map of uveitis and a foundation for studying the cellular and molecular mechanisms and pathogenesis of this disease.

2023-07-10 | GSE236389 | GEO

Single-cell transcriptomic analysis of retinal immune regulation and blood-retinal barrier function during experimental autoimmune uveitis

Project description:Uveitis is characterised by breakdown of the blood-retinal barrier (BRB), allowing infiltration of immune cells that mediate intraocular inflammation, which can lead to irreversible damage of the neuroretina and the loss of sight. Treatment of uveitis relies heavily on corticosteroids and systemic immunosuppression due to limited understanding of the molecular immune interactions that underpin ocular immune homeostasis. By performing single-cell transcriptomic analysis of whole dissociated mouse retinas with experimental autoimmune uveitis (EAU) versus healthy control, we gained an unbiased appreciation of the immune interactions that drive retinal inflammation in a model of posterior uveitis.

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Genome expression profile for CD3+ T cells treated by nimodipine in EAU model

Project description:Uveitis is a severe autoimmune disease characereized by retinal inflammation, whicn brings harms to the visual function of the patients. We found that nimodipine could protect annimals from experimental autoimmune uveitis. To further clarify the possible mechanism through which nimodipine exerted effect, we performed genomic expression profiling of CD3+ T cells in EAU model and nimodipine treated group.

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Murine CD4+ T cells: naive vs. experimental autoimmune uveitis

Project description:miRNA expression profiling of CD4+ T cells comparing naïve mice and experimental autoimmune uveitis (EAU) mice. EAU was induced by immunization of retinal antigen (IRBP1-20) in complete Freund’s adjuvant (CFA). CD4+ T cells were isolated and purified from the spleen and draining lymph nodes 13 days after immunization.

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Retinal endothelial cell phenotypic modifications during experimental autoimmune uveitis: a transcriptomic approach

Project description:Background: Blood-retinal barrier cells are known to exhibit a massive phenotypic change during experimental autoimmune uveitis (EAU) development. In an attempt to investigate the mechanisms of blood-retinal barrier (BRB) breakdown at a global level, we studied the gene regulation of total retinal cells and retinal endothelial cells during non-infectious uveitis. Methods: Retinal endothelial cells were isolated by flow cytometry either in Tie2-GFP mice (CD31+ CD45- GFP+ cells), or in wild type C57BL/6 mice (CD31+ CD45- endoglin+ cells). EAU was induced in C57BL/6 mice by adoptive transfer of IRBP1-20-specific T cells. Total retinal cells and retinal endothelial cells from naïve and EAU mice were sorted and their gene expression compared by RNA-Seq. Protein expression of selected genes was validated by immunofluorescence on retinal wholemounts and cryosections and by flow cytometry. Results: Retinal endothelial cell sorting in wild type C57BL/6 mice was validated by comparative transcriptome analysis with retinal endothelial cells sorted from Tie2-GFP mice, which express GFP under the control of the endothelial-specific receptor tyrosine kinase promoter Tie2. RNA-Seq analysis of total retinal cells mainly brought to light upregulation of genes involved in antigen presentation and T cell activation during EAU. Specific transcriptome analysis of retinal endothelial cells allowed us to identify 82 genes modulated in retinal endothelial cells during EAU development. Protein expression of 5 of those genes (serpina3n, lipocalin 2, ackr1, lrg1 and lamc3) was validated at the level of inner BRB cells. Conclusion: Those data not only confirm the involvement of known pathogenic molecules but further provide a list of new candidate genes and pathways possibly implicated in inner BRB breakdown during non-infectious posterior uveitis.

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Single-cell RNA sequencing reveals CD74high CCL5high retinal microglia initiating immune cells infiltration in autoimmune uveoretinitis

Project description:In this study, we found that microglia have a considerable number of cells compared to T cells, indicating an equally critical role of microglia in the progression of autoimmune uveitis. We further identified a specific microglial subpopulation expressed with high levels of CD74 and CCL5, which may be directly related to inflammation regulation in autoimmune uveitis and named inflammation-associated microglia (IAMs). Decreasing the number of IAMs by gene regulation methods or CD74/CCL5 neutralizing antibodies effectively reduced inflammation in EAU mice and delayed disease progression. A mechanistic study indicated that the CD74/CCL5 axis was mainly responsible for the regulation of the immune response in autoimmune uveitis. The intracytoplasmic domain of CD74 (CD74–ICD) may be cleaved by the SPPL2A protease and then activate the NF-kB-dependent inflammation pathway in IAM, resulting in the production of CCL5, which recruits peripheral T cells into the retina and causes an inflammatory burst in autoimmune uveitis mice. Decreasing the level of CD74 or CCL5 could effectively reduce uveitogenic T cell infiltration and relieve the autoimmune response in EAU mouse models, indicating the potential therapeutic value of CD74 and CCL5 in autoimmune uveitis.

2022-11-11 | GSE191260 | GEO

Ikzf1 lactylation regulates CD4 T cell differentiation

Project description:Dysregulation of Th17 differentiation was implicated in multiple inflammatory and autoimmune diseases including autoimmune uveitis. In the current study, we have provided evidence indicating that lactate-derived lactylation plays important roles in regulating Th17 differentiation. The lactylation level of CD4+ T cells was upregulated in EAU mice and inhibiting lactylation resulted in impaired EAU progression. We characterized the global lactylome of CD4+ T cells of normal and EAU mice. We found that the differentially lactylated proteins were enriched in pathways related to immune responses including leukocyte differentiation. Importantly, our results show that the lactylation level of Ikzf1 (K164) functions in regulating Th17 differentiation by differentially modulating gene expression patterns which are related to CD4+ T cell differentiation by CUT& Tag analysis. In view of the above mentioned well-documented evidence, Ikzf1 lactylation might represent an important regulator for Th17 differentiation in autoimmune uveitis.

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Effector T cells driving monophasic vs relapse/remitting experimental autoimmune uveitis show unique pathway signatures

Project description:Experimental autoimmune uveitis (EAU) in Lewis rats is a model for the clinical heterogeneity of human uveitis. The autoantigens inducing disease in the rat are also seen in human disease. Depending upon the specific autoantigen used, the experimental disease course can be either monophasic or relapsing/remitting and appears to be dictated by the T cell effector phenotype elicited. We investigated potential differences between monophasic and relapsing/remitting effector T cells using transcriptomic profiling and pathway analysis. RNA samples isolated from three independent T cell lines derived from each specificity where analyzed by microarrays. Microarray data was used to obtain transcriptomic changes reflecting signal transduction pathway dysregulation. Keywords: Two group comparison Comparison of two types of cell lines of two different antigen specificities.

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The cytokine IL-17A limits Th17 pathogenicity via a negative feedback loop driven by autocrine induction of IL-24

Project description:Dysregulated Th17 cell responses underlie multiple inflammatory and autoimmune diseases, including autoimmune uveitis and its animal model, EAU. However, clinical trials targeting IL-17A in uveitis were not successful. Here, we found that Th17 cells were regulated by their own signature cytokine, IL-17A. Loss of IL-17A in autopathogenic Th17 cells did not reduce their pathogenicity and instead elevated their expression of the Th17 cell cytokines GM-CSF and IL-17F. Mechanistic in vitro studies revealed a Th17 cell-intrinsic autocrine loop triggered by binding of IL-17A to its receptor, leading to activation of transcription factor NFκB and induction of IL 24, which repressed the Th17 cytokine program. In vivo, IL-24 treatment ameliorated Th17-induced EAU, whereas silencing of IL-24 in Th17 cells enhanced disease. This regulatory pathway also operated in human Th17 cells. Thus, IL-17A limits pathogenicity of Th17 cells by inducing IL-24. These findings may explain the disappointing therapeutic effect in targeting IL-17A in uveitis.

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Murine retina: Control vs. experimental autoimmune uveoretinitis

Project description:Transcriptional profiling of mouse retina comparing naïve mouse and experimental autoimmune uveoretinitis (EAU)-developing mouse. EAU was induced by immunization of retinal autoantigens in adjuvants. Retinas were harvested 14 days after immunization.

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