Triptolide analog LLDT-8 ameliorates psoriasis-like dermatitis in BALB/c mice via suppressing the IL-36α signaling pathway

Qing Qi; Qian Li; Hongwen Zhu; Huimin Lu; Xiaoqian Yang; Yanwei Wu; Chunlan Feng; Chen Fan; Heng Li; Bing Wu; Yuanzhuo Gao; Zongwang Zhang; Hu Zhou; Jianping Zuo; Wei Tang

doi:10.1016/j.phrs.2021.105678

Triptolide analog LLDT-8 ameliorates psoriasis-like dermatitis in BALB/c mice via suppressing the IL-36α signaling pathway

Pharmacol Res. 2021 Jul:169:105678. doi: 10.1016/j.phrs.2021.105678. Epub 2021 May 17.

Authors

Qing Qi¹, Qian Li², Hongwen Zhu³, Huimin Lu⁴, Xiaoqian Yang⁵, Yanwei Wu⁶, Chunlan Feng⁷, Chen Fan⁸, Heng Li⁹, Bing Wu¹⁰, Yuanzhuo Gao¹¹, Zongwang Zhang¹², Hu Zhou¹³, Jianping Zuo¹⁴, Wei Tang¹⁵

Affiliations

¹ Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: qiqing007@126.com.
² Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Life Sciences, Shanghai University, Shanghai 201203, China. Electronic address: 1310688209@qq.com.
³ Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: zhw@simm.ac.cn.
⁴ Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Pharmacy, University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: 201628012342137@simm.ac.cn.
⁵ Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: xqyang@simm.ac.cn.
⁶ Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: wuyanwei@simm.ac.cn.
⁷ Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: clfeng@simm.ac.cn.
⁸ Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: fanchen@simm.ac.cn.
⁹ Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Pharmacy, University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: liheng@simm.ac.cn.
¹⁰ Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Pharmacy, University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: 201728012342054@simm.ac.cn.
¹¹ Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Pharmacy, University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: 13651994735@163.com.
¹² Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Life Sciences, Shanghai University, Shanghai 201203, China. Electronic address: 1043950598@qq.com.
¹³ Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: zhouhu@simm.ac.cn.
¹⁴ Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: jpzuo@simm.ac.cn.
¹⁵ Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: tangwei@simm.ac.cn.

PMID: 34015449
DOI: 10.1016/j.phrs.2021.105678

Abstract

Triptolide has shown a good immunosuppressive effect on autoimmune diseases. However, the toxicity limited its widely clinical practice. In this study, we investigated the effects and underlying mechanisms of (5R)-5-hydroxytriptolide (LLDT-8), a novel triptolide derivative, on a murine psoriasis-like dermatitis model and related cell lines. Here, we showed that LLDT-8 significantly attenuated symptoms of psoriasis-like dermatitis induced by imiquimod (IMQ, a TLR7 agonist) by reducing the psoriasis area and severity index (PASI) score and inflammatory parameters. The action of LLDT-8 was involved in down-regulated interleukin (IL)-36α expression and blocked IL-36α pathway by LC-MS-based label-free quantitative (LFQ) proteomic approach and further experiments. Meanwhile, we observed that LLDT-8 significantly inhibited the expression of IL-36α in R837-treated bone marrow-derived dendritic cells (BMDCs). In conclusion, LLDT-8 notably alleviated IMQ-induced psoriasis-like skin inflammation via suppressing the IL-36α signaling pathway, suggesting LLDT-8 might be a potential drug for the treatment of psoriasis.

Keywords: IL-36α; IL-36α pathway; Inflammation; LLDT-8; Psoriasis; Triptolide.

Publication types

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

MeSH terms

Animals
Blotting, Western
Cell Line
Dermatitis / drug therapy*
Dermatitis / metabolism
Dermatologic Agents / therapeutic use*
Disease Models, Animal
Diterpenes / therapeutic use*
Female
Flow Cytometry
Humans
Interleukin-1 / antagonists & inhibitors*
Interleukin-1 / metabolism
Mice
Mice, Inbred BALB C
Psoriasis / drug therapy*
Psoriasis / metabolism
Signal Transduction / drug effects*
Skin / drug effects
Skin / metabolism

Substances

5-hydroxytriptolide
Dermatologic Agents
Diterpenes
Interleukin-1
interleukin 1F6, mouse