Pemphigus vulgaris (PV) is an autoimmune blistering skin disease characterized by suprabasal acantholysis produced as a consequence of desmoglein (Dsg) and non-Dsg autoantibodies binding to several targeting molecules localized on the membrane of keratinocytes. Nitric oxide (NO) may exert a pathogenic function in several immunological processes. We have previously demonstrated that neural nitric oxide synthase (nNOS) plays part in PV acantholysis. Also, our group has described a relevant role for HER [human epidermal growth factor receptor (EGFR) related] isoforms and several kinases such as Src (Rous sarcoma), mammalian target of rapamycin (mTOR) and focal adhesion kinase (FAK), as well as caspases in PV development. Using a passive transfer mouse model of PV, we aimed to investigate the relationship between the increase in nNOS and EGFR, Src, mTOR and FAK kinase upregulation observed in PV lesions. Our results revealed a new function for nNOS, which contributes to EGFR-mediated PV acantholysis through the upregulation of Src, mTOR and FAK. In addition, we found that nNOS participates actively in PV at least in part by increasing caspase-9 and caspase-3 activities. These findings underline the important issue that in PV acantholysis, caspase activation is a nNOS-linked process downstream of Src, mTOR and FAK kinase upregulation.

译文

寻常型天疱疮 (PV) 是一种自身免疫性水疱性皮肤病,其特征是由于desmoglein (Dsg) 和非Dsg自身抗体结合到位于角质形成细胞膜上的几种靶向分子而产生的基底上棘皮溶解。一氧化氮 (NO) 可能在几个免疫过程中发挥致病功能。我们以前已经证明神经一氧化氮合酶 (nNOS) 在PV棘层分解中起作用。此外,我们的小组还描述了HER [人表皮生长因子受体 (EGFR) 相关] 亚型和几种激酶的相关作用,例如Src (Rous肉瘤),雷帕霉素的哺乳动物靶标 (mTOR) 和粘着斑激酶 (FAK),以及PV开发中的caspase。使用PV的被动转移小鼠模型,我们旨在研究在PV病变中观察到的nNOS增加与EGFR,Src,mTOR和FAK激酶上调之间的关系。我们的结果揭示了nNOS的新功能,它通过Src,mTOR和FAK的上调促进了EGFR介导的PV棘皮分解。此外,我们发现nNOS至少部分通过增加caspase-9和caspase-3活动来积极参与PV。这些发现强调了一个重要问题,即在PV棘层分解中,caspase激活是Src,mTOR和FAK激酶上调下游的nNOS连接过程。

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