Bullous Pemphigoid IgG Induces Cell Dysfunction and Enhances the Motility of Epidermal Keratinocytes via Rac1/Proteasome Activation
Bullous Pemphigoid IgG Induces Cell Dysfunction and Enhances the Motility of Epidermal Keratinocytes via Rac1/Proteasome Activation
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DOI：
10.3389/fimmu.2019.00200
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发表时间：
2019-02-12
影响因子：
7.3
通讯作者：
Morita, Eishin
中科院分区：
文献类型：
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作者：
Tie, Duerna;Da, Xia;Morita, Eishin
大疱性类天疱疮（BP）是一种以水疱形成为特征的自身免疫性疾病，其中自身抗体主要靶向基底角质形成细胞中表达的XVII型胶原（ColXVII）。已知BP IgG通过巨胞饮作用诱导ColXVII从角质形成细胞的质膜内化。然而，ColXVII内化后的细胞动力学尚未完全阐明。BP IgG对培养的角质形成细胞产生精确的作用，BP IgG刺激的细胞中的形态/功能变化导致与BP发病机制相关的表皮下起泡。基于电子显微镜检查，BP IgG刺激的细胞表现出细胞膜结构的改变和细胞内囊泡的积累。BP IgG刺激的细胞中的这些形态学变化伴随着线粒体功能障碍、活性氧产生增加、运动性增加和脱离。BP IgG触发级联反应，导致代谢障碍，并刺激处理的角质形成细胞中的细胞迁移。这些细胞的改变被Rac 1或蛋白酶体途径的药理学抑制剂逆转，表明Rac 1和蛋白酶体活化参与BP IgG对培养的角质形成细胞的影响。我们的研究强调了角质形成细胞动力学在BP患者中IgG直接功能中的作用。
Bullous pemphigoid (BP) is an autoimmune disease characterized by the formation of blisters, in which autoantibodies mainly target type XVII collagen (ColXVII) expressed in basal keratinocytes. BP IgG is known to induce the internalization of ColXVII from the plasma membrane of keratinocytes through macropinocytosis. However, the cellular dynamics following ColXVII internalization have not been completely elucidated. BP IgG exerts a precise effect on cultured keratinocytes, and the morphological/functional changes in BP IgG-stimulated cells lead to the subepidermal blistering associated with BP pathogenesis. Based on the electron microscopy examination, BP IgG-stimulated cells exhibit alterations in the cell membrane structure and the accumulation of intracellular vesicles. These morphological changes in the BP IgG-stimulated cells are accompanied by dysfunctional mitochondria, increased production of reactive oxygen species, increased motility, and detachment. BP IgG triggers the cascade leading to metabolic impairments and stimulates cell migration in the treated keratinocytes. These cellular alterations are reversed by pharmacological inhibitors of Rac1 or the proteasome pathway, suggesting that Rac1 and proteasome activation are involved in the effects of BP IgG on cultured keratinocytes. Our study highlights the role of keratinocyte kinetics in the direct functions of IgG in patients with BP.