Background Nakajo-Nishimura syndrome (NNS) is an immunoproteasome-associated autoinflammatory disorder caused by a mutation of PSMB8 gene.1 Although dysfunction of immunoproteasome causes various cellular stresses attributed to the overproduction of inflammatory cytokines and chemokine in NNS, precise underlying mechanisms of autoinflammation are still largely unknown.
Objectives We aim to investigate and understand the detailed mechanisms and signal pathways in NNS and to seek potential therapeutic candidates.
Methods We established a panel of isogenic pluripotent stem cell (PSC) lines with the homozygous G201V mutation in PSMB8 gene using CRISPR/Cas9- mediated genome editing system. Myeloid cell lines (MLs) were established from each clone and used for functional analysis.2 3
Results Immunoproteasome activity of PSMB8-mutant PSC-derived MLs (MTMLs) reduced even without stimulation, compared to that of the isogenic wild-type counterparts. When stimulated, MT-MLs showed overproduction of inflammatory cytokines and chemokines, with elevated reactive oxygen species (ROS). The levels of phosphorylated p38 MAPK and STAT1 also increased. Treatment with a p38 MAPK inhibitor, a JAK inhibitor and anti-oxidants dose-dependently decreased the abnormal production of cytokines and chemokines in MT-MLs. Both unstimulated and stimulated MT-MLs showed distinct transcriptional profiles, indicating the ML-MLs were already in a ‘primed’ state before stimulation.
Conclusions The current PSC models revealed a specific ROS-mediated inflammatory pathway and provide a platform for studying the pathophysiology of NNS and searching for the alternative therapeutic options for NNS and related immunoproteasome disorders.
References  Arima K, et al. PNAS2011;108(36):14914–9.
 Kawasaki Y, et al. Arthritis Rheum2017;69(2):447–459.
 Takada S, et al. J Allergy Clin Immunol2018;141(1):339–349.
Acknowledgements We thank Dr. Fumiko Honda-Ozaki and Ms Madoka Terashima for conducting researdch. We also thank Drs. Nobuo Kanazawa, Akira Niwa, Masakatsu Yanagimachi, Akitsu Hotta and Tatsutoshi Nakahata, and Ms. Haruna Ito for percitipating. Funding was provided by Japan Agency for Medical Research and Development, Tokyo, Japan.
Disclosure of Interest None declared
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.