Topical TYK2 inhibitor ameliorates psoriasis-like dermatitis via the AKT-SP1-NGFR-AP1 pathway in keratinocytes

IF 7.9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine Pub Date : 2025-03-04 DOI:10.1002/ctm2.70256

Zhiqin Fang, Rundong Jiang, Yutong Wang, Wangqing Chen, Xiang Chen, Mingzhu Yin

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Abstract

Introduction

Tyrosine kinase 2 (TYK2)-dependent cytokine signalling is integral to the pathogenesis of psoriasis. While BMS-986165, a highly selective TYK2 inhibitor, has recently been approved for oral treatment of psoriasis, its therapeutic potential via topical application remains unexplored.

Objectives

We aim to investigate the efficacy of topically applying TYK2 inhibitor in psoriasis and to elucidate the underlying mechanisms driving the therapeutic effects of this delivery approach.

Methods

1.5% BMS-986165 ointment was applied topically to the back skin of imiquimod (IMQ)-induced psoriatic mice. To identify potential target cells influenced by the topical TYK2 inhibitor, we performed single cell RNA sequencing (scRNA-seq) and flow cytometry on mouse lesions. The role of TYK2 in vitro was assessed by silencing its expression or administering BMS-986165 in human keratinocytes (KCs). Mechanistic insights into TYK2 function in KCs were further investigated using RNA-seq, dual luciferase reporter assay and ChIP-qPCR.

Results

External use of 1.5% BMS-986165 ointment significantly ameliorated the IMQ-induced psoriasis-like dermatitis. Importantly, topical TYK2 inhibitor attenuated proinflammatory capability of KCs. In vitro, TYK2 inhibition suppressed the transcription of nerve growth factor receptor (NGFR) by disrupting the AKT-SP1 signalling pathway. This impairment hindered the activation of activator protein 1 (AP1), thereby weakening the proinflammatory potential of KCs.

Conclusion

This study reveals a novel therapeutic potential for selective TYK2 inhibitor in topical manner on psoriasis therapy, which might prompt the development of topical treatment for psoriasis. Crucially, our findings provide an underexplored regulatory mechanism of TYK2 inhibitor in psoriasis.

Key points

Topical TYK2 inhibitor alleviates psoriasis-like dermatitis.
Topical TYK2 inhibitor reduces psoriasis progression through restraining the inflammatory responses of keratinocytes.
The inhibition of TYK2 regulates the inflammatory response of keratinocytes through AKT-SP1-NGFR-AP1 pathway.

Abstract Image

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局部TYK2抑制剂通过角质形成细胞中的AKT-SP1-NGFR-AP1途径改善银屑病样皮炎

酪氨酸激酶2 （TYK2）依赖的细胞因子信号传导是牛皮癣发病机制的组成部分。虽然BMS-986165是一种高选择性TYK2抑制剂，最近已被批准用于口服治疗银屑病，但其通过局部应用的治疗潜力仍未被探索。我们的目的是研究局部应用TYK2抑制剂治疗银屑病的疗效，并阐明驱动这种给药方法治疗效果的潜在机制。方法将1.5% BMS-986165软膏局部涂于咪喹莫特（IMQ）诱导的银屑病小鼠背部皮肤。为了鉴定受局部TYK2抑制剂影响的潜在靶细胞，我们对小鼠病变进行了单细胞RNA测序（scRNA-seq）和流式细胞术。通过沉默TYK2的表达或在人角质形成细胞（KCs）中给药BMS-986165来评估TYK2在体外的作用。利用RNA-seq、双荧光素酶报告基因检测和ChIP-qPCR进一步研究了TYK2在KCs中的功能机制。结果1.5% BMS-986165软膏外用可显著改善imq诱导的银屑病样皮炎。重要的是，局部TYK2抑制剂可以减弱KCs的促炎能力。在体外，TYK2抑制通过破坏AKT-SP1信号通路抑制神经生长因子受体（NGFR）的转录。这种损伤阻碍了激活蛋白1 （activator protein 1, AP1）的激活，从而削弱了KCs的促炎潜能。结论本研究揭示了选择性TYK2抑制剂局部治疗银屑病的新潜力，可能促进银屑病局部治疗的发展。至关重要的是，我们的研究结果提供了TYK2抑制剂在银屑病中的调节机制。局部TYK2抑制剂可缓解银屑病样皮炎。局部TYK2抑制剂通过抑制角质形成细胞的炎症反应来减少银屑病的进展。TYK2的抑制通过AKT-SP1-NGFR-AP1通路调节角质形成细胞的炎症反应。

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.