Topical VX-509 attenuates psoriatic inflammation through the STAT3/FABP5 pathway in keratinocytes

Bei Yan; Panpan Liu; Xiaoqin Yi; Jie Li; Nian Liu; Wu Zhu; Yehong Kuang; Xiang Chen; Cong Peng

doi:10.1016/j.phrs.2022.106318

Topical VX-509 attenuates psoriatic inflammation through the STAT3/FABP5 pathway in keratinocytes

Pharmacol Res. 2022 Aug:182:106318. doi: 10.1016/j.phrs.2022.106318. Epub 2022 Jun 18.

Authors

Bei Yan¹, Panpan Liu¹, Xiaoqin Yi¹, Jie Li¹, Nian Liu¹, Wu Zhu¹, Yehong Kuang¹, Xiang Chen¹, Cong Peng²

Affiliations

¹ The Department of Dermatology, Xiangya Hospital, Central South University, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, China.
² The Department of Dermatology, Xiangya Hospital, Central South University, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, China; Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, China. Electronic address: pengcongxy@csu.edu.cn.

PMID: 35728766
DOI: 10.1016/j.phrs.2022.106318

Abstract

Background: Psoriasis is a chronic inflammatory disease, with lesions mainly manifesting as scaly erythematous plaques. The mild or moderate of psoriasis is the main type of patients in hospital, and topical application remains the preferred treatment option for psoriasis therapy, therefore, the development of novel topical agents has an essential role in psoriasis therapy.

Objective: To identify potential drugs for psoriasis topical treatment.

Methods: We performed drug screening by Imiquimod (IMQ)-induced psoriatic like inflammation in mouse model, followed mouse epidermis by RNA-seq to find the key molecules affecting the drug. The qRT-PCR, WB were performed to test mRNA and protein expression, and Chip assay had been conducted to examine Stat3 bound to promoter of FABP5.

Results: In this study, we identified VX-509, which topical application significantly attenuated IMQ-induced psoriatic like inflammation in mouse model. And then, we verified Epidermal Fatty acid binding protein (E-FABP/FABP5) was significantly decreased in VX-509 treated mouse epidermis by RNA-seq. FABP5 is a key molecule in lipid metabolism, administration of FABP5 inhibitor or knock down of FABP5 expression remarkably abrogated psoriatic inflammation as well as lipid metabolism. Mechanistically, our finding showed that VX-509 blocked IL-22 induced signaling pathway, particular in activation of Stat3. Furthermore, we identified Stat3 is a transcriptional factor associated with FABP5 promoters and VX-509 treatment remarkably attenuated IL-22-induced FABP5 expression through Stat3 in KCs.

Conclusions: This study demonstrated administration of VX-509 is a potential promising topical drug for treatment of psoriasis, FABP5 is a critical targeted molecule in psoriasis therapy.

Keywords: AT9283 (PubChem CID:135398495); AZD1480 (PubChem CID:16659841); BMS-911543 (PubChem CID:50922691); CYT387 (PubChem CID:25062766); FABP5; Filgotinib (PubChem CID:49831257); IL-22; Psoriasis; STAT3; TG101209 (PubChem CID:16722832); Topical application treatment; VX-509; VX-509 (PubChem CID:59422203); WHI-P154 (PubChem CID:3795).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Disease Models, Animal
Fatty Acid-Binding Proteins / genetics
Fatty Acid-Binding Proteins / metabolism
Fatty Acid-Binding Proteins / therapeutic use
Heterocyclic Compounds, 2-Ring
Imiquimod / metabolism
Inflammation / metabolism
Keratinocytes* / metabolism
Mice
Mice, Inbred BALB C
Neoplasm Proteins / metabolism
Psoriasis* / chemically induced
Psoriasis* / drug therapy
STAT3 Transcription Factor / metabolism
Skin / pathology
Valine / analogs & derivatives

Substances

2-((2-(1H-pyrrolo(2,3-b)pyridin-3-yl)pyrimidin-4-yl)amino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide
Fabp5 protein, mouse
Fatty Acid-Binding Proteins
Heterocyclic Compounds, 2-Ring
Neoplasm Proteins
STAT3 Transcription Factor
Stat3 protein, mouse
Valine
Imiquimod