Topical TYK2 inhibitor ameliorates psoriasis-like dermatitis via the AKT-SP1-NGFR-AP1 pathway in keratinocytes
Zhiqin Fang
Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China
National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Central South University, Changsha, Hunan, China
Search for more papers by this authorRundong Jiang
Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China
National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Central South University, Changsha, Hunan, China
Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA
Search for more papers by this authorYutong Wang
Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China
Clinical Medicine Eight-Year Program, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
Search for more papers by this authorWangqing Chen
Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China
National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Central South University, Changsha, Hunan, China
Search for more papers by this authorCorresponding Author
Xiang Chen
Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China
National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Central South University, Changsha, Hunan, China
Correspondence
Xiang Chen and Mingzhu Yin, Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Email: [email protected] and [email protected]
Search for more papers by this authorCorresponding Author
Mingzhu Yin
Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China
National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Central South University, Changsha, Hunan, China
Clinical Research Center, Medical Pathology Center, Cancer Early Detection and Treatment Center, Chongqing University Three Gorges Hospital, Chongqing University, Wanzhou, Chongqing, China
Correspondence
Xiang Chen and Mingzhu Yin, Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Email: [email protected] and [email protected]
Search for more papers by this authorZhiqin Fang
Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China
National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Central South University, Changsha, Hunan, China
Search for more papers by this authorRundong Jiang
Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China
National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Central South University, Changsha, Hunan, China
Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA
Search for more papers by this authorYutong Wang
Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China
Clinical Medicine Eight-Year Program, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
Search for more papers by this authorWangqing Chen
Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China
National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Central South University, Changsha, Hunan, China
Search for more papers by this authorCorresponding Author
Xiang Chen
Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China
National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Central South University, Changsha, Hunan, China
Correspondence
Xiang Chen and Mingzhu Yin, Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Email: [email protected] and [email protected]
Search for more papers by this authorCorresponding Author
Mingzhu Yin
Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China
National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Central South University, Changsha, Hunan, China
Clinical Research Center, Medical Pathology Center, Cancer Early Detection and Treatment Center, Chongqing University Three Gorges Hospital, Chongqing University, Wanzhou, Chongqing, China
Correspondence
Xiang Chen and Mingzhu Yin, Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Email: [email protected] and [email protected]
Search for more papers by this authorZhiqin Fang, Rundong Jiang and Yutong Wang contributed equally to this work.
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
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Topical TYK2 inhibitor alleviates psoriasis-like dermatitis.
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Topical TYK2 inhibitor reduces psoriasis progression through restraining the inflammatory responses of keratinocytes.
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The inhibition of TYK2 regulates the inflammatory response of keratinocytes through AKT-SP1-NGFR-AP1 pathway.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflicts of interest.
Open Research
DATA AVAILABILITY STATEMENT
The data underlying this article will be shared on reasonable request from the corresponding author.
Supporting Information
| Filename | Description |
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| ctm270256-sup-0001-SuppMat.docx1.3 MB | Supporting information |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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