Pluripotent Stem Cell Model of Nakajo-Nishimura Syndrome Untangles Proinflammatory Pathways Mediated by Oxidative Stress.
Pluripotent Stem Cell Model of Nakajo-Nishimura Syndrome Untangles Proinflammatory Pathways Mediated by Oxidative Stress.
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DOI：
10.1016/j.stemcr.2018.04.004
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发表时间：
2018-06-05
影响因子：
5.9
通讯作者：
Saito MK
中科院分区：
文献类型：
--
作者：
Honda-Ozaki F;Terashima M;Niwa A;Saiki N;Kawasaki Y;Ito H;Hotta A;Nagahashi A;Igura K;Asaka I;Li HL;Yanagimachi M;Furukawa F;Kanazawa N;Nakahata T;Saito MK
Nakajo-Nishimura综合征（NNS）是一种由PSMB 8基因突变引起的免疫蛋白酶体相关自身炎症性疾病。虽然免疫蛋白酶体功能障碍导致各种细胞应激归因于过度生产的炎性细胞因子和趋化因子在NNS中，自身炎症的潜在机制仍然在很大程度上是未知的。为了研究和理解NNS的机制和信号通路，我们建立了一组具有PSMB 8突变的等基因多能干细胞（PSC）系。与非突变型ML相比，即使没有刺激，PSMB 8突变型PSC衍生的骨髓细胞系（MT-ML）中免疫蛋白酶体的活性也降低。此外，MT-ML显示炎性细胞因子和趋化因子的过度产生，活性氧（ROS）和磷酸化p38 MAPK水平升高。用p38 MAPK抑制剂和抗氧化剂处理减少了细胞因子和趋化因子的异常产生。目前的PSC模型揭示了一个特定的ROS介导的炎症途径，为发现NNS和相关免疫蛋白酶体疾病的替代治疗方案提供了一个平台。制备了用于Nakajo-Nishimura综合征的同基因PSC组。突变骨髓细胞系显示促炎反应增加，p38 MAPK抑制剂和抗氧化剂治疗恢复了促炎表型。建立了一组来自多能干细胞的永生化骨髓细胞系，所述多能干细胞在PSMB 8基因中具有Nakajo-Nishimura综合征（NNS）相关突变。这些细胞系概括了疾病表型，并揭示了氧化应激和p38 MAPK通路对自身炎症的作用。
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. An isogenic PSC panel for Nakajo-Nishimura syndrome was prepared Mutant myeloid cell lines showed increased proinflammatory response p38 MAPK inhibitor and antioxidant treatment restored the proinflammatory phenotype To reveal the pathophysiology of a proteasome-associated autoinflammatory syndrome, Honda-Ozaki et al. established a panel of immortalized myeloid cell lines from pluripotent stem cells harboring a Nakajo-Nishimura syndrome (NNS)-associated mutation in the PSMB8 gene. The lines recapitulated disease phenotypes and revealed the role of oxidative stress and the p38 MAPK pathway on autoinflammation.
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