Inhibition of dipeptidyl-peptidase 4 induces upregulation of the late cornified envelope cluster in keratinocytes.
Inhibition of dipeptidyl-peptidase 4 induces upregulation of the late cornified envelope cluster in keratinocytes.
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二肽基肽酶4的抑制作用诱导晚期晶状体包膜簇的上调。
DOI：
10.1007/s00403-021-02249-4
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发表时间：
2022-11
影响因子：
3
通讯作者：
中科院分区：
文献类型：
--
作者：
二肽基肽酶4（DPP 4）是一种多功能的II型跨膜糖蛋白，表达于多种细胞表面。虽然DPP 4抑制剂在糖尿病治疗中具有治疗作用，但它们是大疱性类天疱疮发生的独立风险因素。因此，有报道称DPP 4抑制可改善银屑病。我们研究了DPP 4抑制对原代人角质形成细胞的影响，以确定DPP 4是否调节角质形成细胞炎症信号传导和角质形成细胞稳态。我们对用DPP 4抑制剂处理的原代成人角质形成细胞进行了RNA测序，鉴定了424个差异表达基因。基因本体分析显示，表皮分化和皮层包膜基因显着富集。使用三维器官型培养物和泛晚期皮质包膜2（LCE 2）抗体，我们证明了在表皮发育过程中DPP 4抑制和LCE 2表达增加之间的剂量依赖关系。晚期皮质包膜基因簇在上皮发育的晚期表达，对钙和紫外线等刺激作出反应。虽然其生物学功能尚未完全了解，但LCE 3B/LCE 3C突变使斑块状银屑病的发生风险增加40%。虽然我们没有发现角质形成细胞炎症标志物的显著调节，但DPP 4抑制增加晚期皮质包膜的表达可能为银屑病提供潜在的替代治疗机制。
Dipeptidyl-peptidase 4 (DPP4) is a multifunctional type II transmembrane glycoprotein that is expressed on various cell surfaces. While DPP4 inhibitors have a therapeutic role in the treatment of diabetes mellitus, they are an independent risk factor in the development of bullous pemphigoid. Contrarily, there are reports of improvement in psoriasis with DPP4 inhibition. We investigated the effect of DPP4 inhibition on primary human keratinocytes to determine whether DPP4 modulates keratinocyte inflammatory signaling and keratinocyte homeostasis. We performed RNA sequencing of primary adult human keratinocytes treated with DPP4 inhibitor, identifying 424 differentially expressed genes. Gene ontology analysis revealed significant enrichment of epidermal differentiation and cornified envelope genes. Using three-dimensional organotypic cultures and a pan-late cornified envelope 2 (LCE2) antibody, we demonstrate a dose dependent relationship between DPP4 inhibition and increased expression of LCE2 during epidermal development. The late cornified envelope gene clusters are expressed at the late stages of epithelial development, responding to stimuli such as calcium and ultraviolet light. While its biologic function is not fully understood, mutations in LCE3B/LCE3C confer a 40% increased risk in the development of plaque psoriasis. While we did not identify significant modulation of keratinocyte inflammatory markers, DPP4 inhibition increased expression of the late cornified envelope may offer a potential alternative therapeutic mechanism in psoriasis.
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影响因子：
10.3
作者：
Novelli, M;Savoia, P;Bernengo, MG
通讯作者：
Bernengo, MG
影响因子：
4.4
作者：
Kridin, Khalaf;Amber, Kyle;Cohen, Arnon D.
通讯作者：
Cohen, Arnon D.
影响因子：
14.8
作者：
通讯作者：
--
影响因子：
3
作者：
van Lingen, R. G.;Poll, M. K. P.;van Erp, P. E. J.
通讯作者：
van Erp, P. E. J.
影响因子：
10.3
作者：
van Lingen, R. G.;de Kerkhof, P. C. M. van;van Erp, P. E. J.
通讯作者：
van Erp, P. E. J.