Pluripotent Stem Cell Model of Nakajo-Nishimura Syndrome Untangles Proinflammatory Pathways Mediated by Oxidative Stress

• 尾﨑(本田), 富美子

  Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University

• 寺嶋, 聖佳

  Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University

• 丹羽, 明

  Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University

• 佐伯, 憲和

  Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University

• 川崎, ゆり

  Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University

• 堀田, 秋津

  Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University

• 浅香, 勲

  Department of Life Science Frontiers, Center for iPS Cell Research and Application

• 中畑, 龍俊

  Department of Fundamental Cell Technology, Center for iPS Cell Research and Application, Kyoto University

• 斎藤, 潤

  Department of Fundamental Cell Technology, Center for iPS Cell Research and Application, Kyoto University

• Asaka, Isao

  Department of Fundamental Cell Technology, Center for iPS Cell Research and Application, Kyoto University

• Li, Hongmei Lisa

  Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University・Boston Children's Hospital, Harvard Medical School

• Yanagimachi, Masakatsu

  Department of Pediatrics, Tokyo Medical and Dental University

• Furukawa, Fukumi

  Department of Dermatology, Wakayama Medical University

• Kanazawa, Nobuo

  Department of Dermatology, Wakayama Medical University

• Nakahata, Tatsutoshi

  Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University

• Saito, Megumu K.

  Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University

抄録

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.

収録刊行物

• Stem cell reports

  Stem cell reports 10 (6), 1835-1850, 2018-06-05

  Elsevier BV

キーワード

• Nakajo-Nishimura syndrome (NNS)
• proteasome subunit beta type 8 (PSMB8)
• disease-specific induced pluripotent stem cells
• reactive oxygen species (ROS)
• myeloid cells

詳細情報

• CRID: 1050282810837038976
• NII論文ID: 120006491981
• ISSN: 22136711
• DOI: 10.1016/j.stemcr.2018.04.004
• HANDLE: 2433/233014
• Web Site: https://api.elsevier.com/content/article/PII:S2213671118301723?httpAccept=text/xml
• Web Site: https://api.elsevier.com/content/article/PII:S2213671118301723?httpAccept=text/plain
• 本文言語コード: en
• 資料種別: journal article
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