Lycorine ameliorates bleomycin-induced pulmonary fibrosis via inhibiting NLRP3 inflammasome activation and pyroptosis

Qing Liang; Wuyang Cai; Yaxue Zhao; Huanbai Xu; Huirong Tang; Daijie Chen; Feng Qian; Lei Sun

doi:10.1016/j.phrs.2020.104884

Lycorine ameliorates bleomycin-induced pulmonary fibrosis via inhibiting NLRP3 inflammasome activation and pyroptosis

Pharmacol Res. 2020 Aug:158:104884. doi: 10.1016/j.phrs.2020.104884. Epub 2020 May 16.

Authors

Qing Liang¹, Wuyang Cai², Yaxue Zhao², Huanbai Xu³, Huirong Tang², Daijie Chen², Feng Qian⁴, Lei Sun⁵

Affiliations

¹ Department of Pharmacy, Shanghai Fifth People's Hospital, Fudan University, Shanghai, 200240, China.
² Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China.
³ Department of Endocrinology and Metabolism, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, 100 Haining Road, Shanghai, China.
⁴ Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China; Anhui Province Key Laboratory of Translational Cancer Research, Bengbu Medical College, Bengbu, Anhui Province, 233003, China. Electronic address: fengqian@sjtu.edu.cn.
⁵ Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China. Electronic address: sunlei_vicky@sjtu.edu.cn.

PMID: 32428667
DOI: 10.1016/j.phrs.2020.104884

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic and irreversible lung disease with limited therapeutic strategies. Lycorine (LYC), an alkaloid isolated from Amaryllidaceae family plants, exhibits effective anti-inflammatory, antiviral, and anti-tumor activities. In this study, we attempted to determine the effect of LYC on bleomycin (BLM)-induced IPF and NLRP3 inflammasome activation. Our results demonstrated that the LYC treatment ameliorated BLM-induced pulmonary fibrosis and inflammation in mice. LYC inhibited active Caspase-1 expression and lactate dehydrogenase (LDH) release during BLM-induced acute lung injury (ALI) in mice. Furthermore, our in vitro assay showed that LYC inhibited LPS/Nigericin- or LPS/ATP-induced NACHT, LRP and PYD domains-containing protein 3 (NLRP3) inflammasome activation, and pyroptosis in bone marrow-derived macrophages (BMDMs). Mechanically, LYC could disturb the interaction of NLRP3 with apoptosis-associated speck-like protein containing a CARD (ASC) by targeting the pyrin domain (PYD) on Leu9, Leu50, and Thr53. Our findings indicate that LYC ameliorated BLM-induced pulmonary fibrosis by inhibiting NLRP3 inflammasome activation and pyroptosis through targeting the PYD domain of ASC. Thus, LYC might be a potential therapeutic agent for pulmonary inflammation and fibrosis.

Keywords: Lycorine; NLRP3 inflammasome; Pulmonary fibrosis; Pyroptosis.

Publication types

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

MeSH terms

Amaryllidaceae Alkaloids / chemistry
Amaryllidaceae Alkaloids / pharmacology
Amaryllidaceae Alkaloids / therapeutic use*
Animals
Antibiotics, Antineoplastic / toxicity
Bleomycin / toxicity*
Cell Survival / drug effects
Cell Survival / physiology
Cells, Cultured
Dose-Response Relationship, Drug
HEK293 Cells
Humans
Male
Mice
Mice, Inbred C57BL
Molecular Docking Simulation / methods
NLR Family, Pyrin Domain-Containing 3 Protein / antagonists & inhibitors*
NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
Phenanthridines / chemistry
Phenanthridines / pharmacology
Phenanthridines / therapeutic use*
Protein Structure, Secondary
Pulmonary Fibrosis / chemically induced*
Pulmonary Fibrosis / drug therapy*
Pulmonary Fibrosis / metabolism
Pyroptosis / drug effects*
Pyroptosis / physiology

Substances

Amaryllidaceae Alkaloids
Antibiotics, Antineoplastic
NLR Family, Pyrin Domain-Containing 3 Protein
Nlrp3 protein, mouse
Phenanthridines
Bleomycin
lycorine