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Series GSE98454 Query DataSets for GSE98454
Status Public on Jan 24, 2018
Title Pluripotent stem cell models of Blau syndrome reveal an IFN-<gamma>-dependent inflammatory response in macrophages
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary Background: Blau syndrome, or early-onset sarcoidosis, is a juvenile-onset systemic granulomatosis associated with a mutation in Nucleotide-binding oligomerization domain 2 (NOD2). The underlying mechanisms of Blau syndrome leading to autoinflammation are still unclear, and there is currently no effective specific treatment for Blau syndrome.
Objectives: To elucidate the mechanisms of autoinflammation in Blau syndrome, we sought to clarify the relation between disease associated-mutant NOD2 and the inflammatory response in human samples.
Methods: Blau syndrome-specific induced pluripotent stem cells (iPSCs) lines were established. To precisely evaluate the in vitro phenotype of iPSC-derived cells, the disease-associated NOD2 mutation of iPSCs was corrected using a CRISPR/Cas9 system. We also introduced the same NOD2 mutation into a control iPSC line. These isogenic iPSCs were then differentiated into monocytic cell lineages, and the status of NF-κB pathway and proinflammatory cytokine secretion were investigated.
Results: We focused on the signals that upregulate the expression of NOD2, especially IFN-γ signaling. IFN-γ treatment of NOD2-mutant macrophages induced ligand-independent NF-κB activation and proinflammatory cytokine production. IFN-γ treatment acted as a priming signal through the up-regulation of NOD2 protein and recruitment of NOD2 on the basement membrane. Conversely, the production of proinflammatory cytokines by MDP, a ligand of NOD2, was decreased in mutant macrophages.
Conclusions: Our data support the significance of ligand-independent autoinflammation in the pathophysiology of Blau syndrome. Our comprehensive isogenic disease-specific iPSC panel provides a useful platform for probing therapeutic and diagnostic clues for the treatment of Blau syndrome patients.
Overall design RNA-sequencing was conducted to identify the genes expressed in reponse to stimulation in different manners between WT and MT cells
Contributor(s) Takada S, Niwa A, Saito M
Citation(s) 28587749
Submission date May 02, 2017
Last update date Jul 25, 2021
Contact name Akira Niwa
Organization name CiRA, Kyoto University
Department Department of Clinical Application
Street address 53, Shogoin-Kawahara-cho, Sakyo-ku
City Kyoto
ZIP/Postal code 6068306
Country Japan
Platforms (1)
GPL18460 Illumina HiSeq 1500 (Homo sapiens)
Samples (12)
GSM2596469 RNA-seq_Blau2-R334W_IFN-γ
GSM2596471 RNA-seq_Blau2-R334W_IFN-γ+MDP
GSM2596473 RNA-seq_Blau2-R334W_untreated
BioProject PRJNA385133
SRA SRP106049

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Supplementary file Size Download File type/resource
GSE98454_RAW.tar 15.0 Mb (http)(custom) TAR (of TXT)
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Raw data are available in SRA
Processed data provided as supplementary file

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