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Fibroblasts to Keratinocytes Redox Signaling: The Possible Role of ROS in Psoriatic Plaque Formation

机译:成纤维细胞对角质形成细胞的氧化还原信号:银屑病斑块形成中ROS的可能作用。

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摘要

Although the role of reactive oxygen species-mediated (ROS-mediated) signalling in physiologic and pathologic skin conditions has been proven, no data exist on the skin cells ROS-mediated communication. Primary fibroblasts were obtained from lesional and non-lesional skin of psoriatic patients. ROS, superoxide anion, calcium and nitric oxide levels and lipoperoxidation markers and total antioxidant content were measured in fibroblasts. NADPH oxidase activity and NOX1, 2 and 4 expressions were assayed and NOX4 silencing was performed. Fibroblasts and healthy keratinocytes co-culture was performed. MAPK pathways activation was studied in fibroblasts and in co-cultured healthy keratinocytes. Increased intracellular calcium, •NO and ROS levels as well as an enhanced NADPH oxidase 4 (NOX4)–mediated extracellular ROS release was shown in lesional psoriatic vs. control fibroblasts. Upon co-culture with lesional fibroblasts, keratinocytes showed p38 and ERK MAPKs pathways activation, ROS, Ca and •NO increase and cell cycle acceleration. Notably, NOX4 knockdown significantly reduced the observed effects of lesional fibroblasts on keratinocyte cell cycle progression. Co-culture with non-lesional psoriatic and control fibroblasts induced slight cell cycle acceleration, but notable intracellular ROS accumulation and ERK MAPK activation in keratinocytes. Collectively, our data demonstrate that NOX4 expressed in dermal fibroblasts is essential for the redox paracrine regulation of epidermal keratinocytes proliferation.
机译:尽管已经证明了活性氧介导的(ROS介导的)信号在生理和病理皮肤状况中的作用,但是关于皮肤细胞ROS介导的通讯尚无数据。原发性成纤维细胞获自牛皮癣患者的病变和非病变皮肤。测量成纤维细胞中的ROS,超氧阴离子,钙和一氧化氮水平以及脂过氧化标记和总抗氧化剂含量。测定NADPH氧化酶活性以及NOX1、2和4的表达,并进行NOX4沉默。进行成纤维细胞和健康的角质形成细胞共培养。在成纤维细胞和共培养的健康角质形成细胞中研究了MAPK途径的激活。在皮损性银屑病患者和对照性成纤维细胞中,发现细胞内钙,•NO和ROS水平升高,以及NADPH氧化酶4(NOX4)介导的细胞外ROS释放增强。与病灶成纤维细胞共培养后,角质形成细胞显示出p38和ERK MAPK途径活化,ROS,Ca和•NO增加以及细胞周期加速。值得注意的是,NOX4敲低显着降低了病变成纤维细胞对角质形成细胞周期进程的影响。与非病灶性牛皮癣和对照成纤维细胞共培养可诱导轻微的细胞周期加速,但在角质形成细胞中细胞内ROS积累和ERK MAPK活化显着。总体而言,我们的数据表明,真皮成纤维细胞中表达的NOX4对于氧化还原旁分泌调节表皮角质形成细胞增殖至关重要。

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