NFAT1 Regulates Systemic Autoimmunity through the Modulation of a Dendritic Cell Property

Chae, Chang-Suk; Kim, Gi-Cheon; Park, Eun Sil; Lee, Choong-Gu; Verma, Ravi; Cho, Hagg-Lim; Jun, Chang‐Duk; Yoo, Yung Joon; Im, Sungbin

doi:10.4049/jimmunol.1700882

Cited by 9 publications

(7 citation statements)

References 59 publications

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“…Function annotation and KEGG pathway enrichment analysis showed that the upregulated DEGs were mainly enriched in apoptotic process, type I interferon signaling pathway, inflammatory response, TNF signaling pathway and NF-kappa B signaling pathway; while the downregulated DEGs were mainly involved in oxidation-reduction process, antigen processing, regulation of release of sequestered calcium ion into cytosol, lysosome and HTLV–I infection. This is consistent with the knowledge that the NF-kappa B signaling pathway, TNF signaling pathway and type I interferon signaling pathway are the main pathway for mDCs ( 20 – 24 ). These results indicated that the DEGs were mainly focused on the immune response.…”

Section: Discussionsupporting

confidence: 92%

Identification of key genes and pathways in regulating immune‑induced diseases of dendritic cells by bioinformatic analysis

Yang

Zheng

et al. 2018

Mol Med Report

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Dendritic cells (DCs) serve crucial roles in the activation of the immune response, and imbalance in the activation or inhibition of DCs has been associated with an increased susceptibility to develop immune-induced diseases. However, the molecular mechanisms of regulating immune-induced diseases of DCs are not well understood. The aim of the present study was to identify the gene signatures and uncover the potential regulatory mechanisms in DCs. A total of 4 gene expression profiles (GSE52894, GSE72893, GSE75938 and GSE77969) were integrated and analyzed in depth. In total, 241 upregulated genes and 365 downregulated genes were detected. Gene ontology and pathway enrichment analysis showed that the differentially expressed genes (DEGs) were significantly enriched in the inflammatory response, the tumor necrosis factor (TNF) signaling pathway, the nuclear factor (NF)-κB signaling pathway and antigen processing. The top 10 hub genes were identified from the protein-protein analysis. The most significant 2 modules were filtered from the protein-protein network. The genes in 2 modules were involved in type I interferon signaling, the NF-κB signaling pathway and the TNF signaling pathway. Furthermore, the microRNA-mRNA network analysis was performed. The results of the present study revealed that the identified DEGs and pathways may improve our understanding of the mechanisms of the maturation of DCs, and the candidate hub genes that may be therapeutic targets for immune-induced diseases.

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Section: Discussionsupporting

confidence: 92%

Identification of key genes and pathways in regulating immune‑induced diseases of dendritic cells by bioinformatic analysis

Yang

Zheng

et al. 2018

Mol Med Report

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“…Moreover, NFATC3 regulates polarization of inflammatory M1 macrophages (42). By modulating the effects of IRF1, MYC, and STAT1 and the functions of inflammatory myeloid cells, and by suppressing NF-κB hyperactivation, NFATC2 regulates both acute and chronic inflammation (43). Determining whether such methylome changes mediate the presence of B and T lymphocytes, and plasma cells in the corona surrounding urate crystals in tophi (5), is germane to elucidating the fundamental processes of tissue urate crystal deposition, which might be modulated by crystal-bound immunoglobulin.…”

Section: Discussionmentioning

confidence: 99%

Differential DNA Methylation of Networked Signaling, Transcriptional, Innate and Adaptive Immunity, and Osteoclastogenesis Genes and Pathways in Gout

Wang

Zhao

Phipps‐Green

et al. 2020

Arthritis & Rheumatology

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Objective. In gout, autoinflammatory responses to urate crystals promote acute arthritis flares, but the pathogeneses of tophi, chronic synovitis, and erosion are less well understood. Defining the pathways of epigenomic immunity training can reveal novel pathogenetic factors and biomarkers. The present study was undertaken to seminally probe differential DNA methylation patterns utilizing epigenome-wide analyses in patients with gout.Methods. Peripheral blood mononuclear cells (PBMCs) were obtained from a San Diego cohort of patients with gout (n = 16) and individually matched healthy controls (n = 14). PBMC methylome data were processed with ChAMP package in R. ENCODE data and Taiji data analysis software were used to analyze transcription factor (TF)-gene networks. As an independent validation cohort, whole blood DNA samples from New Zealand Māori subjects (n = 13 patients with gout, n = 16 control subjects without gout) were analyzed.Results. Differentially methylated loci clearly separated gout patients from controls, as determined by hierarchical clustering and principal components analyses. IL23R, which mediates granuloma formation and cell invasion, was identified as one of the multiple differentially methylated gout risk genes. Epigenome-wide analyses revealed differential methylome pathway enrichment for B and T cell receptor signaling, Th17 cell differentiation and interleukin-17 signaling, convergent longevity regulation, circadian entrainment, and AMP-activated protein kinase signaling, which are pathways that impact inflammation via insulin-like growth factor 1 receptor, phosphatidylinositol 3-kinase/Akt, NF-κB, mechanistic target of rapamycin signaling, and autophagy. The gout cohorts overlapped for 37 (52.9%) of the 70 TFs with hypomethylated sequence enrichment and for 30 (78.9%) of the 38 enriched KEGG pathways identified via TFs. Evidence of shared differentially methylated gout TF-gene networks, including the NF-κB activation-limiting TFs MEF2C and NFATC2, pointed to osteoclast differentiation as the most strongly weighted differentially methylated pathway that overlapped in both gout cohorts.Conclusion. These findings of differential DNA methylation of networked signaling, transcriptional, innate and adaptive immunity, and osteoclastogenesis genes and pathways suggest that they could serve as novel therapeutic targets in the management of flares, tophi, chronic synovitis, and bone erosion in patients with gout.

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“…2F. It is well-known that NFAT1 transcription factor regulates speci c functions of DCs such as tolerance and T cell differentiation [27,28], however to the best of our knowledge this is the rst direct evidence in support of this signalling in DC upon TREM2 engagement.…”

Section: Transcriptional Regulation Of Intracellular Trem2 Signaling By Sulf Amentioning

confidence: 91%

Identification of Sulfavant A as the First Synthetic TREM2 Ligand Discloses a Homeostatic Response of Dendritic Cells After Receptor Engagement

Gallo

Manzo

Barra

et al. 2022

Preprint

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The immune response arises from a fine balance of cellular and molecular mechanisms that provide for surveillance, tolerance, and elimination of dangers as pathogens. Improving the quality of the immune response remains a major goal in immunotherapy and vaccine development. Sulfavant A (SULF A) is a sulfolipid that has shown promising adjuvant activity in a cancer vaccine model. Here we report that SULF A is the first synthetic small molecule binding to the Triggering Receptor Expressed on Myeloid cells-2 (TREM2). The receptor engagement initiates an unconventional maturation of Dendritic cells (DCs) leading to upregulation of the Major Histocompatibility Complex class II (MHC Class II) and costimulatory molecules (CD83, CD86, DC54) without release of T helper type 1 (Th1) or 2 (Th2) cytokines. According to a TREM2 mechanism, this response is mediated by SYK-NFAT axis and is compromised by blockade and gene silencing of the receptor. Activation by SULF A preserved the DC functions to excite the allogeneic T cell response, and induced interleukin-10 (IL-10) release after lipopolysaccharide (LPS) stimulation. These results well support the adjuvant effect of SULF A and offer novel insights into the role of TREM2 in the differentiation of an unprecedented DC phenotype (homeDCs) that contributes to the maintenance of immune homeostasis without compromising lymphocyte activation and immunogenic response. The biological function of SULF-A may be of interest in various physiological and pathological processes involving the immune system.

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NFAT1 Regulates Systemic Autoimmunity through the Modulation of a Dendritic Cell Property

Cited by 9 publications

References 59 publications

Identification of key genes and pathways in regulating immune‑induced diseases of dendritic cells by bioinformatic analysis

Identification of key genes and pathways in regulating immune‑induced diseases of dendritic cells by bioinformatic analysis

Differential DNA Methylation of Networked Signaling, Transcriptional, Innate and Adaptive Immunity, and Osteoclastogenesis Genes and Pathways in Gout

Identification of Sulfavant A as the First Synthetic TREM2 Ligand Discloses a Homeostatic Response of Dendritic Cells After Receptor Engagement

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