Pluripotent Stem Cell Model of Nakajo-Nishimura Syndrome Untangles Proinflammatory Pathways Mediated by Oxidative Stress
| Autor: | Fumiko Honda-Ozaki, Haruna Ito, Hongmei Lisa Li, Nobuo Kanazawa, Isao Asaka, Ayako Nagahashi, Tatsutoshi Nakahata, Fukumi Furukawa, Akitsu Hotta, Yuri Kawasaki, Megumu K. Saito, Masakatsu Yanagimachi, Norikazu Saiki, Koichi Igura, Madoka Terashima, Akira Niwa |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Pluripotent Stem Cells
0301 basic medicine Proteasome Endopeptidase Complex Chemokine disease-specific induced pluripotent stem cells p38 mitogen-activated protein kinases Biology medicine.disease_cause reactive oxygen species (ROS) Models Biological p38 Mitogen-Activated Protein Kinases Biochemistry Article Proinflammatory cytokine Fingers Interferon-gamma 03 medical and health sciences Erythema Nodosum Genetics medicine Humans Induced pluripotent stem cell chemistry.chemical_classification Reactive oxygen species Mutation Gene Expression Profiling PSMB8 Cell Differentiation Cell Biology proteasome subunit beta type 8 (PSMB8) Oxidative Stress 030104 developmental biology chemistry myeloid cells biology.protein Cancer research Reactive Oxygen Species Transcriptome Nakajo-Nishimura syndrome (NNS) Biomarkers Oxidative stress Signal Transduction Developmental Biology |
| Zdroj: | Stem Cell Reports |
| ISSN: | 2213-6711 |
| Popis: | Summary Nakajo-Nishimura syndrome (NNS) is an immunoproteasome-associated autoinflammatory disorder caused by a mutation of the PSMB8 gene. Although dysfunction of the immunoproteasome causes various cellular stresses attributed to the overproduction of inflammatory cytokines and chemokines in NNS, the underlying mechanisms of the autoinflammation are still largely unknown. To investigate and understand the mechanisms and signal pathways in NNS, we established a panel of isogenic pluripotent stem cell (PSC) lines with PSMB8 mutation. Activity of the immunoproteasome in PSMB8-mutant PSC-derived myeloid cell lines (MT-MLs) was reduced even without stimulation compared with non-mutant-MLs. In addition, MT-MLs showed an overproduction of inflammatory cytokines and chemokines, with elevated reactive oxygen species (ROS) and phosphorylated p38 MAPK levels. Treatment with p38 MAPK inhibitor and antioxidants decreased the abnormal production of cytokines and chemokines. The current PSC model revealed a specific ROS-mediated inflammatory pathway, providing a platform for the discovery of alternative therapeutic options for NNS and related immunoproteasome disorders. Highlights • An isogenic PSC panel for Nakajo-Nishimura syndrome was prepared • Mutant myeloid cell lines showed increased proinflammatory response • p38 MAPK inhibitor and antioxidant treatment restored the proinflammatory phenotype To reveal the pathophysiology of a proteasome-associated autoinflammatory syndrome, Honda-Ozaki et al. established a panel of immortalized myeloid cell lines from pluripotent stem cells harboring a Nakajo-Nishimura syndrome (NNS)-associated mutation in the PSMB8 gene. The lines recapitulated disease phenotypes and revealed the role of oxidative stress and the p38 MAPK pathway on autoinflammation. |
| Databáze: | OpenAIRE |
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