|
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 |
E-mail(s) |
akiranw@cira.kyoto-u.ac.jp
|
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)
|
|
Relations |
BioProject |
PRJNA385133 |
SRA |
SRP106049 |