Pluripotent stem cell models of Blau syndrome reveal an IFN-γ–dependent inflammatory response in macrophages

Takada, Shinako; Kambe, Naotomo; Kawasaki, Yoshihisa; Niwa, Akira; Honda‐Ozaki, Fumiko; Kobayashi, Kazuki; Osawa, Mitsujiro; Nagahashi, Ayako; Semi, Katsunori; Hotta, Akitsu; Asaka, Isao; Yamada, Yasuhiro; Nishikomori, Ryuta; Heike, Toshio; Matsue, Hiroyuki; Nakahata, Tatsutoshi; Saito, Megumu K.

doi:10.1016/j.jaci.2017.04.013

Cited by 46 publications

(47 citation statements)

References 40 publications

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“…We previously demonstrated that such MLs can be used to model the proinflammatory phenotypes of various autoinflammatory disorders [14,[28][29][30]. Combined with the current study, which successfully identified candidate compounds, we concluded that this ML-based HTS system provides a versatile platform for screening candidate compounds for treating autoinflammatory disorders.…”

Section: Discussionsupporting

confidence: 64%

High-throughput Screening with Pluripotent Stem Cells Identifies CUDC-907 as an Effective Compound for Restoring the Proinflammatory Phenotype of Nakajo-Nishimura Syndrome

Kase

Terashima

Ohta

et al. 2020

Preprint

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Nakajo-Nishimura syndrome (NNS) is an autoinflammatory disorder caused by a homozygous mutations in PSMB8 gene. The administration of systemic corticosteroids is partially effective, but continuous treatment causes severe side effects. We previously established a pluripotent stem cell (PSC)-derived NNS disease model that reproduces several inflammatory phenotypes including the overproduction of monocyte chemoattractant protein-1 (MCP-1) and interferon gamma-induced protein-10 (IP-10). Here we performed high-throughput compound screening (HTS) using this PSC-derived NNS model to find potential therapeutic candidates and identified CUDC-907 as an effective inhibitor of the release of MCP-1 and IP-10.CUDC-907 did not induce cell death within therapeutic concentrations and was also effective on primary patient cells. Further analysis indicated that the inhibitory effect was post-transcriptional. These findings suggest that HTS with PSC-derived disease models is useful for finding drug candidates for autoinflammatory diseases. Significance statementIn this study, we identified a histone deacetylase inhibitor CUDC-907 as a potential effective compound for ameliorating overproduction of inflammatory chemokines in an autoinflammatory disease named Nakajo-Nishimura syndrome. We performed high-throughput screening using pluripotent stem cell-derived monocytic cell lines. Our data prove the validity of screening system as a versatile platform for seeking candidate compounds for the treatment of congenital immunological disorders associated with monocytic lineage cells.

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Section: Discussionsupporting

confidence: 64%

High-throughput Screening with Pluripotent Stem Cells Identifies CUDC-907 as an Effective Compound for Restoring the Proinflammatory Phenotype of Nakajo-Nishimura Syndrome

Kase

Terashima

Ohta

et al. 2020

Preprint

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“…HASMCs were seeded onto multi-well glass-bottom dishes. The nuclear translocation of NF-κB p65 subunit was evaluated as previously described [ 14 ]. After culture for the indicated time periods, cells were fixed with 4% paraformaldehyde in PBS (−) for 30 min.…”

Section: Methodsmentioning

confidence: 99%

“…HASMCs were transfected with pGreenFire NF-κB transcription reporter lentivector (System Biosciences, Mountain View, CA) inserted with the Renilla gene under the CMV promoter as an internal control [ 14 ]. The NF-κB activity was then measured using the Dual-Luciferase Reporter Assay System (Promega, Madison, WI).…”

Section: Methodsmentioning

confidence: 99%

Lysosomal membrane permeabilization causes secretion of IL-1β in human vascular smooth muscle cells

et al. 2018

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ObjectiveIL-1β secretion by the inflammasome is strictly controlled and requires two sequential signals: a priming signal and an activating signal. Lysosomal membrane permeabilization (LMP) plays a critical role in the regulation of NLRP3 inflammasome, and generally acts as an activating signal. However, the role of LMP controlling NLRP3 inflammasome activation in human vascular smooth muscle cells (hVSMCs) is not well defined.MethodsLMP was induced in hVSMCs by Leu-Leu-O-methyl ester. Cathepsin B was inhibited by CA-074 Me. Cytokine release, mRNA, and protein were quantified by enzyme-linked immunosorbent assay, quantitative PCR, and Western blot, respectively. NF-κB activity was analyzed by immunostaining of the NF-κB p65 nuclear translocation and using the dual-luciferase reporter assay system.ResultsLMP had both priming and activating roles, causing an upregulation of proIL-1β and NLRP3 and the secretion of mature IL-1β from unprimed hVSMCs. LMP activated the canonical NF-κB pathway. The priming effect of LMP was inhibited by CA-074 Me, indicating an upstream role of cathepsin B.ConclusionsThese data support a novel role of LMP as a single stimulus for the secretion of IL-1β from hVSMCs, implying the possibility that hVSMCs are an important initiator of the sterile inflammatory response caused by lysosomal disintegration.

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“…Tangier disease (mutations in ABCA1 ), lysosomal storage diseases including neuronal ceroid lipofuscinoses (NCLs) 27 and Gaucher disease (GD, mutations in GBA ), 28, 29 chronic granulomatous disease (CGD, defective NADPH oxidase), 30 Blau syndrome (mutation in NOD2 ), 31 and chronic infantile neurologic cutaneous and articular syndrome (CINCA syndrome, mutation in NLRP3 ). 32 Some of these studies compared the phenotypes of IPSDM and HMDM derived from the same subjects 8, 29 to further validate the fidelity of IPSDM in assessing the functionality of genetic mutations.…”

Section: Disease Modeling and Functional Genomic Analyses With Ipsdmmentioning

confidence: 99%

Human Induced Pluripotent Stem Cell–Derived Macrophages for Unraveling Human Macrophage Biology

Zhang

Reilly

2017

ATVB

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Despite a substantial appreciation for the critical role of macrophages in cardiometabolic diseases, understanding of human macrophage biology has been hampered by the lack of reliable and scalable models for cellular and genetic studies. Human iPSC-derived macrophages (IPSDM), as an unlimited source of subject genotype-specific cells, will undoubtedly play an important role in advancing our understanding of the role of macrophages in human diseases. In this Review, we summarize current literature in the differentiation and characterization of IPSDM at phenotypic, functional and transcriptomic levels. We emphasize the progress in differentiating iPSC to tissue resident macrophages, and in understanding the ontogeny of in vitro differentiated IPSDM that resembles primitive hematopoiesis, rather than adult definitive hematopoiesis. We review the application of IPSDM in modeling both Mendelian genetic disorders and host-pathogen interactions. Finally, we highlighted the potential areas of research using IPSDM in functional validation of coronary artery disease loci in genome-wide association studies, functional genomic analyses, drug testing and cell therapeutics in cardiovascular diseases.

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Pluripotent stem cell models of Blau syndrome reveal an IFN-γ–dependent inflammatory response in macrophages

Abstract: 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 patients with Blau syndrome.

Cited by 46 publications

References 40 publications

High-throughput Screening with Pluripotent Stem Cells Identifies CUDC-907 as an Effective Compound for Restoring the Proinflammatory Phenotype of Nakajo-Nishimura Syndrome

High-throughput Screening with Pluripotent Stem Cells Identifies CUDC-907 as an Effective Compound for Restoring the Proinflammatory Phenotype of Nakajo-Nishimura Syndrome

Lysosomal membrane permeabilization causes secretion of IL-1β in human vascular smooth muscle cells

Human Induced Pluripotent Stem Cell–Derived Macrophages for Unraveling Human Macrophage Biology

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