scholarly journals Depletion of Retinal Dopaminergic Activity in a Mouse Model of Rod Dysfunction Exacerbates Experimental Autoimmune Uveoretinitis: A Role for the Gateway Reflex

2021 ◽  
Vol 23 (1) ◽  
pp. 453
Author(s):  
Andrea Stofkova ◽  
Miloslav Zloh ◽  
Dominika Andreanska ◽  
Ivana Fiserova ◽  
Jan Kubovciak ◽  
...  
Keyword(s):  
Target Genes ◽  
Immune Cell ◽  
Late Onset ◽  
Transcriptome Profiling ◽  
Cone Dystrophy ◽  
Rod Photoreceptor ◽  
Blood Retinal Barrier ◽  
Dopaminergic Activity ◽  
Experimental Autoimmune Uveoretinitis ◽  
Experimental Autoimmune

The gateway reflex is a mechanism by which neural inputs regulate chemokine expression at endothelial cell barriers, thereby establishing gateways for the invasion of autoreactive T cells into barrier-protected tissues. In this study, we hypothesized that rod photoreceptor dysfunction causes remodeling of retinal neural activity, which influences the blood–retinal barrier and the development of retinal inflammation. We evaluated this hypothesis using Gnat1rd17 mice, a model of night blindness with late-onset rod-cone dystrophy, and experimental autoimmune uveoretinitis (EAU). Retinal remodeling and its effect on EAU development were investigated by transcriptome profiling, target identification, and functional validation. We showed that Gnat1rd17 mice primarily underwent alterations in their retinal dopaminergic system, triggering the development of an exacerbated EAU, which was counteracted by dopamine replacement with L-DOPA administered either systemically or locally. Remarkably, dopamine acted on retinal endothelial cells to inhibit NF-κB and STAT3 activity and the expression of downstream target genes such as chemokines involved in T cell recruitment. These results suggest that rod-mediated dopamine release functions in a gateway reflex manner in the homeostatic control of immune cell entry into the retina, and the loss of retinal dopaminergic activity in conditions associated with rod dysfunction increases the susceptibility to autoimmune uveitis.

scholarly journals Illumination of Molecular Pathways in Multiple Sclerosis Lesions and the Immune Mechanism of Matrine Treatment in EAE, a Mouse Model of MS

2021 ◽  
Vol 12 ◽  
Author(s):  
Mengmeng Dou ◽  
Xueliang Zhou ◽  
Lifeng Li ◽  
Mingliang Zhang ◽  
Wenbin Wang ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Target Genes ◽  
Immune Cell ◽  
Gene Expression Omnibus ◽  
Network Pharmacology ◽  
Autoimmune Encephalomyelitis ◽  
Data Set ◽  
Tissue Samples ◽  
Gene Data ◽  
Experimental Autoimmune

The etiology of multiple sclerosis (MS) is not clear, and the treatment of MS presents a great challenge. This study aimed to investigate the pathogenesis and potential therapeutic targets of MS and to define target genes of matrine, a quinolizidine alkaloid component derived from the root of Sophorae flavescens that effectively suppressed experimental autoimmune encephalomyelitis (EAE), an animal model of MS. To this end, the GSE108000 gene data set in the Gene Expression Omnibus Database, which included 7 chronic active MS lesions and 10 control samples of white matter, was analyzed for differentially expressed genes (DEGs). X cell was used to analyze the microenvironmental differences in brain tissue samples of MS patients, including 64 types of immune cells and stromal cells. The biological functions and enriched signaling pathways of DEGs were analyzed by multiple approaches, including GO, KEGG, GSEA, and GSVA. The results by X cell showed significantly increased numbers of immune cell populations in the MS lesions, with decreased erythrocytes, megakaryocytes, adipocytes, keratinocytes, endothelial cells, Th1 cells and Tregs. In GSE108000, there were 637 DEGs, including 428 up-regulated and 209 down-regulated genes. Potential target genes of matrine were then predicted by the network pharmacology method of Traditional Chinese medicine, and 12 key genes were obtained by cross analysis of the target genes of matrine and DEGs in MS lesions. Finally, we confirmed by RT-PCR the predicted expression of these genes in brain tissues of matrine-treated EAE mice. Among these genes, 2 were significantly downregulated and 6 upregulated by matrine treatment, and the significance of this gene regulation was further investigated. In conclusion, our study defined several possible matrine target genes, which can be further elucidated as mechanism(s) of matrine action, and novel targets in the treatment of MS.

scholarly journals Oligodendrocyte-specific Argonaute profiling identifies microRNAs associated with experimental autoimmune encephalomyelitis

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Qin Ma ◽  
Atsuko Matsunaga ◽  
Brenda Ho ◽  
Jorge R. Oksenberg ◽  
Alessandro Didonna
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Target Genes ◽  
Affinity Purification ◽  
Transcriptome Profiling ◽  
Rna Degradation ◽  
Autoimmune Encephalomyelitis ◽  
Active Involvement ◽  
Purification Technique ◽  
Experimental Autoimmune

Abstract Background MicroRNAs (miRNAs) belong to a class of evolutionary conserved, non-coding small RNAs with regulatory functions on gene expression. They negatively affect the expression of target genes by promoting either RNA degradation or translational inhibition. In recent years, converging studies have identified miRNAs as key regulators of oligodendrocyte (OL) functions. OLs are the cells responsible for the formation and maintenance of myelin in the central nervous system (CNS) and represent a principal target of the autoimmune injury in multiple sclerosis (MS). Methods MiRAP is a novel cell-specific miRNA affinity-purification technique which relies on genetically tagging Argonaut 2 (AGO2), an enzyme involved in miRNA processing. Here, we exploited miRAP potentiality to characterize OL-specific miRNA dynamics in the MS model experimental autoimmune encephalomyelitis (EAE). Results We show that 20 miRNAs are differentially regulated in OLs upon transition from pre-symptomatic EAE stages to disease peak. Subsequent in vitro differentiation experiments demonstrated that a sub-group of them affects the OL maturation process, mediating either protective or detrimental signals. Lastly, transcriptome profiling highlighted the endocytosis, ferroptosis, and FoxO cascades as the pathways associated with miRNAs mediating or inhibiting OL maturation. Conclusions Altogether, our work supports a dual role for miRNAs in autoimmune demyelination. In particular, the enrichment in miRNAs mediating pro-myelinating signals suggests an active involvement of these non-coding RNAs in the homeostatic response toward neuroinflammatory injury.

scholarly journals Absence of S100A4 in the mouse lens induces an aberrant retina-specific differentiation program and cataract

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Rupalatha Maddala ◽  
Junyuan Gao ◽  
Richard T. Mathias ◽  
Tylor R. Lewis ◽  
Vadim Y. Arshavsky ◽  
...  
Keyword(s):  
Calcium Binding ◽  
Late Onset ◽  
Cpg Islands ◽  
Transcriptome Profiling ◽  
Specific Gene ◽  
Pathway Network ◽  
S100a4 Expression ◽  
Histone H3k27 ◽  
Pathway Analyses ◽  
Upregulated Genes

AbstractS100A4, a member of the S100 family of multifunctional calcium-binding proteins, participates in several physiological and pathological processes. In this study, we demonstrate that S100A4 expression is robustly induced in differentiating fiber cells of the ocular lens and that S100A4(−/−) knockout mice develop late-onset cortical cataracts. Transcriptome profiling of lenses from S100A4(−/−) mice revealed a robust increase in the expression of multiple photoreceptor- and Müller glia-specific genes, as well as the olfactory sensory neuron-specific gene, S100A5. This aberrant transcriptional profile is characterized by corresponding increases in the levels of proteins encoded by the aberrantly upregulated genes. Ingenuity pathway network and curated pathway analyses of differentially expressed genes in S100A4(−/−) lenses identified Crx and Nrl transcription factors as the most significant upstream regulators, and revealed that many of the upregulated genes possess promoters containing a high-density of CpG islands bearing trimethylation marks at histone H3K27 and/or H3K4, respectively. In support of this finding, we further documented that S100A4(−/−) knockout lenses have altered levels of trimethylated H3K27 and H3K4. Taken together, our findings suggest that S100A4 suppresses the expression of retinal genes during lens differentiation plausibly via a mechanism involving changes in histone methylation.

scholarly journals Cdx2 regulates immune cell infiltration in the intestine

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Simon Chewchuk ◽  
Sanzida Jahan ◽  
David Lohnes
Keyword(s):  
Intestinal Epithelium ◽  
Target Genes ◽  
Immune Cell ◽  
Cell Number ◽  
Macrophage Infiltration ◽  
Intestinal Homeostasis ◽  
Chronic Inflammatory Response ◽  
Complex Protein ◽  
Inflammatory Phenotype

AbstractThe intestinal epithelium is a unique tissue, serving both as a barrier against pathogens and to conduct the end digestion and adsorption of nutrients. As regards the former, the intestinal epithelium contains a diverse repertoire of immune cells, including a variety of resident lymphocytes, macrophages and dendritic cells. These cells serve a number of roles including mitigation of infection and to stimulate regeneration in response to damage. The transcription factor Cdx2, and to a lesser extent Cdx1, plays essential roles in intestinal homeostasis, and acts as a context-dependent tumour suppressor in colorectal cancer. Deletion of Cdx2 from the murine intestinal epithelium leads to macrophage infiltration resulting in a chronic inflammatory response. However the mechanisms by which Cdx2 loss evokes this response are poorly understood. To better understand this relationship, we used a conditional mouse model lacking all intestinal Cdx function to identify potential target genes which may contribute to this inflammatory phenotype. One such candidate encodes the histocompatability complex protein H2-T3, which functions to regulate intestinal iCD8α lymphocyte activity. We found that Cdx2 occupies the H3-T3 promoter in vivo and directly regulates its expression via a Cdx response element. Loss of Cdx function leads to a rapid and pronounced attenuation of H2-T3, followed by a decrease in iCD8α cell number, an increase in macrophage infiltration and activation of pro-inflammatory cascades. These findings suggest a previously unrecognized role for Cdx in intestinal homeostasis through H2-T3-dependent regulation of iCD8α cells.

Inhibition of cellular transfer of experimental autoimmune uveoretinitis by Rapamycin

1993 ◽  
Vol 1 (3) ◽  
pp. 269-273 ◽  
Author(s):  
FranÇOis G. Roberge ◽  
Alexander Kozhich ◽  
Chi-Chao Chan ◽  
Daniel F. Martin ◽  
Robert B. Nussenblatt ◽  
...  
Keyword(s):  
Experimental Autoimmune Uveoretinitis ◽  
Experimental Autoimmune
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