Pluripotent Stem Cell Model of Nakajo-Nishimura Syndrome Untangles Proinflammatory Pathways Mediated by Oxidative Stress
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Author
Honda-Ozaki, Fumiko
Terashima, Madoka
Niwa, Akira
Saiki, Norikazu
Kawasaki, Yuri
Ito, Haruna
Hotta, Akitsu
Nagahashi, Ayako
Igura, Koichi
Asaka, Isao
Li, Hongmei Lisa
Yanagimachi, Masakatsu
Furukawa, Fukumi
Kanazawa, Nobuo
Nakahata, Tatsutoshi
Saito, Megumu K.
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https://doi.org/10.1016/j.stemcr.2018.04.004Metadata
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Honda-Ozaki, F., M. Terashima, A. Niwa, N. Saiki, Y. Kawasaki, H. Ito, A. Hotta, et al. 2018. “Pluripotent Stem Cell Model of Nakajo-Nishimura Syndrome Untangles Proinflammatory Pathways Mediated by Oxidative Stress.” Stem Cell Reports 10 (6): 1835-1850. doi:10.1016/j.stemcr.2018.04.004. http://dx.doi.org/10.1016/j.stemcr.2018.04.004.Abstract
Summary 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.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989695/pdf/Terms of Use
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