Inhibition of p38MAPK signalling prevents epidermal blistering and alterations of desmosome structure induced by pemphigus autoantibodies in human epidermis
Inhibition of p38MAPK signalling prevents epidermal blistering and alterations of desmosome structure induced by pemphigus autoantibodies in human epidermis
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DOI：
10.1111/bjd.15721
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发表时间：
2017-12-01
影响因子：
10.3
通讯作者：
Waschke, J.
中科院分区：
文献类型：
--
作者：
Egu, D. T.;Walter, E.;Waschke, J.
寻常天疱疮（Pemphigus vulgaris，PV）是由靶向桥粒粘附蛋白桥粒芯蛋白（Desmoglein，Dsg）3和1的自身抗体引起的皮肤水疱性疾病。天疱疮皮肤起泡的机制尚未完全阐明，但p38丝裂原活化蛋白激酶（p38 MAPK）激活是细胞凝聚力完全丧失所必需的信号事件之一。然而，目前还不清楚是否桥粒形态的超微结构标志，观察患者的病变是由p38 MAPK信号转导介导的Objective. ObjectiveIn这项研究中，我们测试了p38 MAPK的水疱形成和超微结构的变化诱导PV自身抗体在人类皮肤中的相关性。（mcPV-IgG），一种来自粘膜显性PV（mdPV-IgG）或AK 23，一种来自天疱疮小鼠模型的致病性单克隆Dsg 3抗体。处理样品进行组织学和电子显微镜analysis.ResultsmcPV-IgG和AK 23，但不是mdPV-IgG减少桥粒大小，引起桥粒间增宽和分裂桥粒的形成，并改变角蛋白丝插入。相比之下，在仅暴露于mcPV-IgG的组织样品中，完整的表皮水疱形成和较低的桥粒数量是明显的。p38 MAPK的药理学抑制钝化桥粒的数量和大小的减少，改善interdesmosomal扩大和角蛋白插入的损失，并防止mcPV-IgG诱导的blister formation.ConclusionsOur数据表明，起泡可以通过抑制p38 MAPK在人表皮。此外，mcPV-IgG诱导的典型形态学改变，如桥粒间增宽和桥粒大小减少，至少部分需要p38 MAPK信号。p38丝裂原活化蛋白激酶（p38 MAPK）抑制剂阻断了角质形成细胞培养物中细胞凝聚力的丧失和寻常型天疱疮自身抗体诱导的小鼠模型中水疱的形成。抑制p38 MAPK信号足以消除皮肤起泡在人类和超微结构的数据表明，p38 MAPK有助于水泡形成通过减少的数量和大小的桥粒和角蛋白丝细胞骨架的调制。什么是翻译的消息？这项研究证明了p38 MAPK信号传导与人类皮肤表皮起泡的相关性，并将此途径与天疱疮患者中发现的桥粒形态学改变联系起来。
BackgroundPemphigus vulgaris (PV) is a skin blistering disease caused by autoantibodies targeting the desmosomal adhesion proteins desmoglein (Dsg) 3 and 1. The mechanisms underlying pemphigus skin blistering are not fully elucidated but p38 mitogen-activated protein kinase (p38MAPK) activation is one of the signalling events necessary for full loss of cell cohesion. However, it is unclear whether ultrastructural hallmarks of desmosome morphology as observed in patients' lesions are mediated by p38MAPK signalling.ObjectivesIn this study, we tested the relevance of p38MAPK for blister formation and the ultrastructural changes induced by PV autoantibodies in human skin.MethodsHuman skin samples were injected with IgG fractions of one patient suffering from mucocutaneous PV (mcPV-IgG), one from mucosal-dominant PV (mdPV-IgG) or AK23, a pathogenic monoclonal Dsg3 antibody derived from a pemphigus mouse model. Samples were processed for histological and electron microscopy analyses.ResultsmcPV-IgG and AK23 but not mdPV-IgG reduced desmosome size, caused interdesmosomal widening and formation of split desmosomes, and altered keratin filament insertion. In contrast, full epidermal blister formation and lower desmosome number were evident in tissue samples exposed to mcPV-IgG only. Pharmacological inhibition of p38MAPK blunted the reduction of desmosome number and size, ameliorated interdesmosomal widening and loss of keratin insertion and prevented mcPV-IgG-induced blister formation.ConclusionsOur data demonstrate that blistering can be prevented by inhibition of p38MAPK in the human epidermis. Moreover, typical morphological alterations induced by mcPV-IgG such as interdesmosomal widening and the reduction of desmosome size at least in part require p38MAPK signalling.What's already known about this topic?p38 mitogen-activated protein kinase (p38MAPK) inhibition blocks loss of cell cohesion in keratinocyte cultures and blister formation in mouse models induced by pemphigus vulgaris autoantibodies.What does this study add?Inhibition of p38MAPK signalling is sufficient to abrogate skin blistering in human and ultrastructural data suggests that p38MAPK contributes to blister formation via reduction of the number and size of desmosomes and modulation of the keratin filament cytoskeleton.What is the translational message?This study demonstrates the relevance of p38MAPK signalling for epidermal blistering in human skin and links this pathway to the alterations of desmosome morphology found in patients with pemphigus.Respond to this article