Liu Yan, Qiao Huan, Zienkiewicz Jozef, Hawiger Jacek
Department of Medicine Division of Allergy Pulmonary and Critical Care Medicine Vanderbilt University School of Medicine Nashville Tennessee USA.
Department of Veterans Affairs Tennessee Valley Health Care System Nashville Tennessee USA.
Skin Health Dis. 2024 Mar 3;4(3):e356. doi: 10.1002/ski2.356. eCollection 2024 Jun.
BACKGROUND: In the two common inflammatory skin diseases, Atopic Dermatitis (AD) and Psoriasis (Ps), keratinocytes (KCs) respond to immune insults through activation of proinflammatory transcription factors (TFs) and their translocation to the cell's nucleus. Therein, the TFs induce expression of genes encoding mediators of skin inflammation. The Nuclear Transport Checkpoint Inhibitors (NTCIs) were developed to regulate nuclear translocation of activated TFs, the essential step of inflammatory response. This new class of cell-penetrating peptide therapeutics controls inflammation caused by allergic, autoimmune, metabolic, and microbial insults. In preclinical model of AD, the treatment with NTCI, cSN50.1 peptide, suppressed the expression of Thymic Stromal Lymphopoietin (), the key gene in the development of allergic inflammation, among the 15 genes silenced by the NTCI. Here, we report the mechanism of anti-inflammatory action of NTCI in human skin-derived KCs. OBJECTIVES: We aimed to determine whether the NTCI treatment can protect human KCs from harmful inflammatory insults. METHODS: Human primary KCs were pretreated with NTCI and challenged with the mix of cytokines Tumour Necrosis Factor alpha (TNF-α) and Interleukin (IL)-17A, or with Phorbol 12-Myristate 13-Acetate (PMA), and analysed for nuclear content of TFs and the expression of genes encoding mediators of inflammation. RESULTS: The nuclear import of TFs, Nuclear Factor ĸB (NF-ĸB) and Signal Transduction and Activator of Transcription 3 (STAT3), was inhibited in cells treated with NTCI. The expression of along with genes encoding the core mediators of inflammation (, , and ) was suppressed by NTCI. Noteworthy, NTCI silenced genes encoding Granulocyte-Macrophage Colony-Stimulating Factor (), and chemokine IL-8 (), responsible for skin infiltration by the eosinophils and other myelomonocytic cells. CONCLUSION: The control of inflammatory response in human KCs by NTCI is attributed to the inhibition of nuclear import of proinflammatory TFs. The protection of human KCs by NTCI, adds new perspectives to the completed Phase two clinical trial of the NTCI (AMTX-100 CF) for AD (NCT04313400).
背景：在两种常见的炎症性皮肤病，特应性皮炎（AD）和银屑病（Ps）中，角质形成细胞（KCs）通过激活促炎转录因子（TFs）并将其转运至细胞核来应对免疫损伤。在细胞核内，这些转录因子诱导编码皮肤炎症介质的基因表达。核转运检查点抑制剂（NTCIs）的研发目的是调节活化转录因子的核转运，这是炎症反应的关键步骤。这类新型的细胞穿透肽疗法可控制由过敏、自身免疫、代谢和微生物损伤引起的炎症。在AD的临床前模型中，用核转运检查点抑制剂cSN50.1肽治疗可抑制胸腺基质淋巴细胞生成素（）的表达，在被核转运检查点抑制剂沉默的15个基因中，该基因是过敏性炎症发展的关键基因。在此，我们报告核转运检查点抑制剂在人皮肤来源的角质形成细胞中的抗炎作用机制。 目的：我们旨在确定核转运检查点抑制剂治疗是否能保护人角质形成细胞免受有害的炎症损伤。 方法：用人原代角质形成细胞预先用核转运检查点抑制剂处理，然后用细胞因子肿瘤坏死因子α（TNF-α）和白细胞介素（IL）-17A混合物或佛波酯12-肉豆蔻酸13-乙酸酯（PMA）进行刺激，并分析转录因子的核含量以及编码炎症介质的基因表达。 结果：在用核转运检查点抑制剂处理的细胞中，转录因子核因子κB（NF-κB）和信号转导及转录激活因子3（STAT3）的核输入受到抑制。核转运检查点抑制剂抑制了与编码炎症核心介质（、和）的基因一起的的表达。值得注意的是，核转运检查点抑制剂使编码粒细胞-巨噬细胞集落刺激因子（）和趋化因子IL-8（）的基因沉默，这两种因子负责嗜酸性粒细胞和其他骨髓单核细胞对皮肤的浸润。 结论：核转运检查点抑制剂对人角质形成细胞炎症反应的控制归因于对促炎转录因子核输入的抑制。核转运检查点抑制剂对人角质形成细胞的保护作用，为已完成的核转运检查点抑制剂（AMTX-100 CF）用于AD的二期临床试验（NCT04313400）增添了新的视角。
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