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

• DOI: 10.1016/j.stemcr.2018.04.004
• Publication Date: 2018-05-03T20:40:53Z
• Authors: 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 Yanagim...; Fukumi Furukawa; Nobuo Kanazawa; Tatsutoshi Nakahata; Megumu K. Saito
• Keywords: Proinflammatory cytokine

Nakajo-Nishimura syndrome (NNS) is an immunoproteasome-associated autoinflammatory disorder caused by a mutation of the PSMB8 gene. Although dysfunction immunoproteasome causes various cellular stresses attributed to overproduction inflammatory cytokines and chemokines in NNS, underlying mechanisms autoinflammation are still largely unknown. To investigate understand signal pathways we established panel isogenic pluripotent stem cell (PSC) lines with mutation. Activity PSMB8-mutant PSC-derived myeloid (MT-MLs) was reduced even without stimulation compared non-mutant-MLs. In addition, MT-MLs showed chemokines, elevated reactive oxygen species (ROS) phosphorylated p38 MAPK levels. Treatment inhibitor antioxidants decreased abnormal production chemokines. The current PSC model revealed specific ROS-mediated pathway, providing platform for discovery alternative therapeutic options NNS related disorders.