Polygala saponins inhibit NLRP3 inflammasome-mediated neuroinflammation via SHP-2-Mediated mitophagy

Wen-Qiao Qiu; Wei Ai; Feng-Dan Zhu; Yue Zhang; Min-Song Guo; Betty Yuen-Kwan Law; Jian-Ming Wu; Vincent Kam-Wai Wong; Yong Tang; Lu Yu; Qi Chen; Chong-Lin Yu; Jian Liu; Da-Lian Qin; Xiao-Gang Zhou; An-Guo Wu

doi:10.1016/j.freeradbiomed.2021.12.263

Polygala saponins inhibit NLRP3 inflammasome-mediated neuroinflammation via SHP-2-Mediated mitophagy

Free Radic Biol Med. 2022 Feb 1:179:76-94. doi: 10.1016/j.freeradbiomed.2021.12.263. Epub 2021 Dec 20.

Authors

Wen-Qiao Qiu¹, Wei Ai², Feng-Dan Zhu³, Yue Zhang⁴, Min-Song Guo⁵, Betty Yuen-Kwan Law⁶, Jian-Ming Wu⁷, Vincent Kam-Wai Wong⁸, Yong Tang⁹, Lu Yu¹⁰, Qi Chen¹¹, Chong-Lin Yu¹², Jian Liu¹³, Da-Lian Qin¹⁴, Xiao-Gang Zhou¹⁵, An-Guo Wu¹⁶

Affiliations

¹ Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou, China; Department of Neurosurgery Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610000, China. Electronic address: fanny.qiu@outlook.com.
² Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou, China. Electronic address: swmuaw@126.com.
³ Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou, China. Electronic address: lethe19970801@163.com.
⁴ Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou, China. Electronic address: zhangyuechanyeol@163.com.
⁵ Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou, China. Electronic address: dididigms@163.com.
⁶ State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macao. Electronic address: yklaw@must.edu.mo.
⁷ Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou, China; Education Ministry Key Laboratory of Medical Electrophysiology, College of Preclinical Medicine, Southwest Medical University, Luzhou, China. Electronic address: jianmingwu@swmu.edu.cn.
⁸ State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macao. Electronic address: kawwong@must.edu.mo.
⁹ Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou, China; State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macao. Electronic address: tangy1989@yeah.net.
¹⁰ Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou, China. Electronic address: yulu863@swmu.edu.cn.
¹¹ Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou, China; Department of Nursing, Affiliated Hospital of Southwest Medical University, Luzhou, China. Electronic address: qichen@swmu.edu.cn.
¹² Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou, China. Electronic address: 8056ycl@swmu.edu.cn.
¹³ Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou, China. Electronic address: belkn@swmu.edu.cn.
¹⁴ Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou, China; Education Ministry Key Laboratory of Medical Electrophysiology, College of Preclinical Medicine, Southwest Medical University, Luzhou, China. Electronic address: dalianqin@swmu.edu.cn.
¹⁵ Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou, China. Electronic address: zxg@swmu.edu.cn.
¹⁶ Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou, China; Education Ministry Key Laboratory of Medical Electrophysiology, College of Preclinical Medicine, Southwest Medical University, Luzhou, China. Electronic address: wuanguo@swmu.edu.cn.

PMID: 34933095
DOI: 10.1016/j.freeradbiomed.2021.12.263

Abstract

Activation of the NLRP3 inflammasome and its mediated neuroinflammation are implicated in neurodegenerative diseases, while mitophagy negatively regulates NLRP3 inflammasome activation. SHP-2, a protein-tyrosine phosphatase, is critical for NLRP3 inflammasome regulation and inflammatory responses. In this study, we investigated whether triterpenoid saponins in Radix Polygalae inhibit the NLRP3 inflammasome via mitophagy induction. First, we isolated the active fraction (polygala saponins (PSS)) and identified 17 saponins by ultra-performance liquid chromatography coupled with diode-array detection and tandem quadrupole time-of-flight mass spectrometry (UHPLC-DAD-Q/TOF-MS). In microglial BV-2 cells, PSS induced mitophagy as evidenced by increased co-localization of LC3 and mitochondria, as well as an increased number of autophagic vacuoles surrounding the mitochondria. Furthermore, the mechanistic study found that PSS activated the AMPK/mTOR and PINK1/parkin signaling pathways via the upregulation of SHP-2. In Aβ(1-42)-, A53T-α-synuclein-, or Q74-induced BV-2 cells, PSS significantly inhibited NLRP3 inflammasome activation, which was attenuated by bafilomycin A1 (an autophagy inhibitor) and SHP099 (an SHP-2 inhibitor). In addition, the co-localization of LC3 and ASC revealed that PSS promoted the autophagic degradation of the NLRP3 inflammasome. Moreover, PSS decreased apoptosis in conditioned medium-induced PC-12 cells. In APP/PS1 mice, PSS improved cognitive function, ameliorated Aβ pathology, and inhibited neuronal death. Collectively, the present study, for the first time, shows that PSS inhibit the NLRP3 inflammasome via SHP-2-mediated mitophagy in vitro and in vivo, which strongly suggests the therapeutic potential of PSS in various neurodegenerative diseases.

Keywords: Mitophagy; NLRP3 inflammasome; Neurodegenerative disease; Polygala saponins; Radix polygalae; SHP-2.

Publication types

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

MeSH terms

Animals
Inflammasomes
Mice
Mitophagy
NLR Family, Pyrin Domain-Containing 3 Protein / genetics
Neuroinflammatory Diseases
Polygala*
Saponins* / pharmacology

Substances

Inflammasomes
NLR Family, Pyrin Domain-Containing 3 Protein
Nlrp3 protein, mouse
Saponins