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Title: Pluripotent Stem Cell Model of Nakajo-Nishimura Syndrome Untangles Proinflammatory Pathways Mediated by Oxidative Stress
Authors: Honda-Ozaki, Fumiko
Terashima, Madoka
Niwa, Akira  kyouindb  KAKEN_id
Saiki, Norikazu
Kawasaki, Yuri
Ito, Haruna
Hotta, Akitsu  kyouindb  KAKEN_id  orcid (unconfirmed)
Nagahashi, Ayako
Igura, Koichi
Asaka, Isao  kyouindb  KAKEN_id
Li, Hongmei Lisa
Yanagimachi, Masakatsu
Furukawa, Fukumi
Kanazawa, Nobuo
Nakahata, Tatsutoshi
Saito, Megumu K.
Author's alias: 尾﨑(本田), 富美子
寺嶋, 聖佳
丹羽, 明
佐伯, 憲和
川崎, ゆり
堀田, 秋津
浅香, 勲
中畑, 龍俊
斎藤, 潤
Keywords: Nakajo-Nishimura syndrome (NNS)
proteasome subunit beta type 8 (PSMB8)
disease-specific induced pluripotent stem cells
reactive oxygen species (ROS)
myeloid cells
Issue Date: 5-Jun-2018
Publisher: Elsevier BV
Journal title: Stem cell reports
Volume: 10
Issue: 6
Start page: 1835
End page: 1850
Abstract: 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.
Rights: © 2018 The Authors. This is an open access article under the CC BY-NC-ND license (
DOI(Published Version): 10.1016/j.stemcr.2018.04.004
PubMed ID: 29731430
Appears in Collections:Journal Articles

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