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

作者：Fumiko Honda‐Ozaki, Madoka Terashima, Akira Niwa, Norikazu Saiki, Yuri Kawasaki, Haruna Ito, Akitsu Hotta, Ayako Nagahashi, Koichi Igura, Isao Asaka, Hongmei Lisa Li, Masakatsu Yanagimachi, Fukumi Furukawa, Nobuo Kanazawa, Tatsutoshi Nakahata, Megumu K. Saito · 发表于：Stem Cell Reports · 年份：2018 · DOI：10.1016/j.stemcr.2018.04.004 · 被引用次数：39 · 研究领域：interferon and immune responses、RNA modifications and cancer、Neutrophil, Myeloperoxidase and Oxidative Mechanisms

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.