Induced pluripotent stem cell-derived monocytic cell lines from a NOMID patient serve as a screening platform for modulating NLRP3 inflammasome activity

Seki, Ryosuke; Ohta, Akira; Niwa, Akira; Sugimine, Yoshinori; Naito, Hiroshi; Nakahata, Tatsutoshi; Saito, Megumu K.

doi:10.1371/journal.pone.0237030

Cited by 12 publications

(17 citation statements)

References 42 publications

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“…Immortalized monocytic cell lines derived from iPSCs of CINCA patients were successfully used to perform HTS of 4,825 compounds and allowed to identify 7 compounds with IL-1β inhibitory activity. The results have proven the validity of the system for identifying drug candidates to treat monocyte/macrophage-associated immunological disorders [ 88 ].…”

Section: Drug Testingmentioning

confidence: 99%

Macrophages derived from pluripotent stem cells: prospective applications and research gaps

Lyadova

Vasiliev

2022

Cell Biosci

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Induced pluripotent stem cells (iPSCs) represent a valuable cell source able to give rise to different cell types of the body. Among the various pathways of iPSC differentiation, the differentiation into macrophages is a recently developed and rapidly growing technique. Macrophages play a key role in the control of host homeostasis. Their dysfunction underlies many diseases, including hereditary, infectious, oncological, metabolic and other disorders. Targeting macrophage activity and developing macrophage-based cell therapy represent promising tools for the treatment of many pathological conditions. Macrophages generated from human iPSCs (iMphs) provide great opportunities in these areas. The generation of iMphs is based on a step-wise differentiation of iPSCs into mesoderm, hematopoietic progenitors, myeloid monocyte-like cells and macrophages. The technique allows to obtain standardizable populations of human macrophages from any individual, scale up macrophage production and introduce genetic modifications, which gives significant advantages over the standard source of human macrophages, monocyte-derived macrophages. The spectrum of iMph applications is rapidly growing. iMphs have been successfully used to model hereditary diseases and macrophage-pathogen interactions, as well as to test drugs. iMph use for cell therapy is another promising and rapidly developing area of research. The principles and the details of iMph generation have recently been reviewed. This review systemizes current and prospective iMph applications and discusses the problem of iMph safety and other issues that need to be explored before iMphs become clinically applicable.

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Section: Drug Testingmentioning

confidence: 99%

Macrophages derived from pluripotent stem cells: prospective applications and research gaps

Lyadova

Vasiliev

2022

Cell Biosci

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“…Out of almost 5,000 tested compounds, seven candidates were sufficiently blocking the IL-1β secretion. Interestingly those were already introduced in previous studies as NLRP3 inhibitors, indicating the effectiveness of the system ( 73 ).…”

Section: Ipsc-based In Vitro Systems To Study Ieimentioning

confidence: 85%

“…generated iPSC-derived immortalized myeloid cell lines from wild-type and NLRP3-mutated iPSC clones and subsequently differentiated these into macrophages ( 73 ). Generated macrophages were further used for developing a high throughput system to identify compounds that show inhibitory effects specifically against the secretion of IL-1β and the activation of mutant NLRP3 ( 73 ). Out of almost 5,000 tested compounds, seven candidates were sufficiently blocking the IL-1β secretion.…”

Section: Ipsc-based In Vitro Systems To Study Ieimentioning

confidence: 99%

In vitro systems to study inborn errors of immunity using human induced pluripotent stem cells

Nikolouli

Reichstein²,

Hansen³

et al. 2022

Front. Immunol.

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In the last two decades, the exponential progress in the field of genetics could reveal the genetic impact on the onset and progression of several diseases affecting the immune system. This knowledge has led to the discovery of more than 400 monogenic germline mutations, also known as “inborn errors of immunity (IEI)”. Given the rarity of various IEI and the clinical diversity as well as the limited available patients’ material, the continuous development of novel cell-based in vitro models to elucidate the cellular and molecular mechanisms involved in the pathogenesis of these diseases is imperative. Focusing on stem cell technologies, this review aims to provide an overview of the current available in vitro models used to study IEI and which could lay the foundation for new therapeutic approaches. We elaborate in particular on the use of induced pluripotent stem cell-based systems and their broad application in studying IEI by establishing also novel infection culture models. The review will critically discuss the current limitations or gaps in the field of stem cell technology as well as the future perspectives from the use of these cell culture systems.

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“…Nevertheless, we observe an overproduction of IL-1β in peripheral blood monocytes extracted from CAPS patients and the macrophages established from CAPS patients-derived induced pluripotent stem (iPS) cells compared to healthy controls ( 18 , 19 ), whereas a reduced response to MDP to produce inflammatory cytokines in the peripheral blood of patients with Blau syndrome were reported ( 20 , 21 ). This lower responsiveness to MDP at the cellular level was also observed in studies using iPS cells differentiated into macrophages established from our patients ( 22 ), or knock-in mice with a corresponding Nod2 mutation identified in Blau syndrome ( 23 ).…”

Section: Molecular Mechanismsmentioning

confidence: 86%

Potential Benefits of TNF Targeting Therapy in Blau Syndrome, a NOD2-Associated Systemic Autoinflammatory Granulomatosis

et al. 2022

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Blau syndrome is a systemic autoinflammatory granulomatous disease caused by mutations in the nucleotide-binding oligomerization domain 2 (NOD2) gene. NOD2 is an intracellular pathogen recognition receptor. Upon binding to muramyl dipeptide (MDP), NOD2 activates the NF-κB pathway, leading to the upregulation of proinflammatory cytokines. Clinical manifestations of Blau syndrome appear in patients before the age of four. Skin manifestations resolve spontaneously in some cases; however, joint and eye manifestations are progressive, and lead to serious complications, such as joint contracture and blindness. Currently, there is no specific curative treatment for the disease. Administration of high-dose oral steroids can improve clinical manifestations; however, treatments is difficult to maintain due to the severity of the side effects, especially in children. While several new therapies have been reported, including JAK inhibitors, anti-IL-6 and anti-IL-1 therapies, anti-TNF therapy plays a central role in the treatment of Blau syndrome. We recently performed an ex vivo study, using peripheral blood and induced pluripotent stem cells from patients. This study demonstrated that abnormal cytokine expression in macrophages from untreated patients requires IFNγ stimulation, and that anti-TNF treatment corrects the abnormalities associated with Blau syndrome, even in the presence of IFNγ. Therefore, although the molecular mechanisms by which the genetic mutations in NOD2 lead to granuloma formation remain unclear, it is possible that prior exposure to TNFα combined with IFNγ stimulation may provide the impetus for the clinical manifestations of Blau syndrome.

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Induced pluripotent stem cell-derived monocytic cell lines from a NOMID patient serve as a screening platform for modulating NLRP3 inflammasome activity

Cited by 12 publications

References 42 publications

Macrophages derived from pluripotent stem cells: prospective applications and research gaps

Macrophages derived from pluripotent stem cells: prospective applications and research gaps

In vitro systems to study inborn errors of immunity using human induced pluripotent stem cells

Potential Benefits of TNF Targeting Therapy in Blau Syndrome, a NOD2-Associated Systemic Autoinflammatory Granulomatosis

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