Dataset Information

Chloroquine modulates inflammatory autoimmune responses through Nurr1 in autoimmune diseases.

ABSTRACT: For over a half-century the anti-malarial drug chloroquine (CQ) has been used as a therapeutic agent, alone or in combination, to treat autoimmune diseases. However, neither the underlying mechanism(s) of action nor their molecular target(s) are well defined. The orphan nuclear receptor Nurr1 (also known as NR4A2) is an essential transcription factor affecting the development and maintenance of midbrain dopaminergic neurons. In this study, using in vitro T cell differentiation models, we demonstrate that CQ activates TREG cell differentiation and induces Foxp3 gene expression in a Nurr1-dependent manner. Remarkably, CQ appears to induce Nurr1 function by two distinct mechanisms: firstly, by direct binding to Nurr1's ligand-binding domain and promoting its transcriptional activity and secondly by upregulation of Nurr1 expression through the CREB signaling pathway. In contrast, CQ suppressed gene expression and differentiation of pathogenic TH17 cells. Importantly, using a valid animal model of inflammatory bowel disease (IBD), we demonstrated that CQ promotes Foxp3 expression and differentiation of TREG cells in a Nurr1-dependent manner, leading to significant improvement of IBD-related symptoms. Taken together, these data suggest that CQ ameliorates autoimmune diseases via regulating Nurr1 function/expression and that Nurr1 is a promising target for developing effective therapeutics of human inflammatory autoimmune diseases.

SUBMITTER: Park TY

PROVIDER: S-EPMC6820774 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Chloroquine modulates inflammatory autoimmune responses through Nurr1 in autoimmune diseases.

Park Tae-Yoon TY Jang Yongwoo Y Kim Woori W Shin Joon J Toh Hui Ting HT Kim Chun-Hyung CH Yoon Ho Sup HS Leblanc Pierre P Kim Kwang-Soo KS

Scientific reports 20191029 1

For over a half-century the anti-malarial drug chloroquine (CQ) has been used as a therapeutic agent, alone or in combination, to treat autoimmune diseases. However, neither the underlying mechanism(s) of action nor their molecular target(s) are well defined. The orphan nuclear receptor Nurr1 (also known as NR4A2) is an essential transcription factor affecting the development and maintenance of midbrain dopaminergic neurons. In this study, using in vitro T cell differentiation models, we demonst ...[more]

PMID: 31664129

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Project description:The current study analyzed gene expression profiles of the endolymphatic sac (ES) in rats and identified expressed genes, present in the human and rat ES, to reveal key hubs for inflammatory responses. Microarray data (accession no. E-MEXP-3022) were obtained from the European Bioinformatics Institute database, including three biological replicates of ES plus dura tissues and three replicates of pure dura tissues form rats. Differentially expressed genes (DEGs) were screened using the Linear Model for Microarray data method and a protein-protein interaction (PPI) network was constructed using data from the Search Tool for the Retrieval of Interacting Genes/Proteins database followed by a module analysis via Clustering with Overlapping Neighborhood Expansion. Function enrichment analysis was performed using the Database for Annotation, Visualization and Integrated Discovery online tool. A total of 612 DEGs were identified, including 396 upregulated and 216 downregulated genes. Gene ontology term enrichment analysis indicated DEGs were associated with cell adhesion, including α5-integrin (Itga1) and secreted phosphoprotein 1 (Spp1); T cell co-stimulation, including C-C chemokine ligand (Ccl)21 and Ccl19; and the toll-like receptor signaling pathway, including toll-like receptor (Tlr)2, Tlr7 and Tlr8. These conclusions were supported by Kyoto Encyclopedia of Genes and Genomes pathway analyses revealing extracellular matrix-receptor interaction, including Itga1 and Spp1; leukocyte transendothelial migration, includingclaudin-4 (Cldn4); and malaria, including Tlr2. The hub roles of Itga1, Cd24 and Spp1 were revealed by calculating three topological properties of the PPI network. Ccl21, Ccl19 and Cldn4 were demonstrated to be crucial following significant module analysis according to the corresponding threshold, which revealed they were enriched in inflammation pathways. Tlr7, Tlr2, granzyme m and Tlr8 were common genes associated with inflammatory responses in rat and human ES. In conclusion, abnormal expression of the aforementioned inflammation-associated genes may be associated with the development of autoimmune inner ear diseases.

Dataset Information

Chloroquine modulates inflammatory autoimmune responses through Nurr1 in autoimmune diseases.

Publications

Chloroquine modulates inflammatory autoimmune responses through Nurr1 in autoimmune diseases.

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