Mechanism of activation of NLRP3 inflammasome by α-synuclein performed fibrils

doi:10.19803/j.1672-8629.20220710

Chinese Journal of Pharmacovigilance ›› 2023, Vol. 20 ›› Issue (4): 409-415.
DOI: 10.19803/j.1672-8629.20220710

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Mechanism of activation of NLRP3 inflammasome by α-synuclein performed fibrils

MA Yidan^1,2, YAN Jiaqing^3Δ, CHU Shifeng², ZHANG Zhao², LIU Yangbo⁴, CHEN Naihong^2#, PENG Can^1,5,6,*

¹School of Pharmacy, Anhui University of Traditional Chinese Medicine, Hefei Anhui 230012, China;
²Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China;
³Department of Pharmacy, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China;
⁴School of Pharmacy, Hunan University of Chinese Medicine, Changsha Hunan 410208, China;
⁵MOE-Anhui Joint Collaborative Innovation Center for Quality Improvement of Anhui Genuine Chinese Medicinal Materials, Hefei Anhui 230012, China;
⁶Anhui Province Key Laboratory of Pharmaceutical Technology and Application, Hefei Anhui 230012, China

Received:2022-12-08 Online:2023-04-15 Published:2023-04-20

Abstract

Abstract: Objective To investigate the mechanism by which fibrillar α-synuclein aggregates induce neuroinflammation by activating NLRP3 inflammasomes. Methods α-synuclein performed fibrils (PFF) was established and added to BV-2 cells. Levels of such inflammatory factors as IL-1β, IL-18, IL-6 and TNF-α as well as protein and mRNA levels of NLRP3, caspase-1 and ASC were detected. LDH release assay was used to investigate pyroptosis. For mechanism research, activation of TLR2 and TLR4 was measured. C29 and TAK-242, inhibitors for TLR2 and TLR4, were used to detect the influence on NLRP3 inflammasome activation mediated by PFF. Results PFF was established as revealed by Western blot and Thioflavin T (ThT) staining. After PFF treatment, NLRP3 inflammasomes were activated in BV-2 cells as evidenced by the release of IL-1β, increased protein levels of NLRP3 and caspase-1 as well as significantly higher mRNA levels of NLRP3, caspase-1 and ASC in the PFF group compared with the control group. However, pyroptosis was not detected in either the PFF group or in the control group. TLR2, but not TLR4, was activated by PFF treatment. Inhibition of TLR2 rather than TLR4 could block PFF induced activation of NLRP3 inflammasomes. Conclusion Fibrillaraα-synuclein aggregates can activate NLRP3 inflammasomes, and the mechanism may be related to the activation of TLR2.

Key words: α-synuclein performed fibrils, NLRP3 inflammasome, TLR2, TLR4

CLC Number:

MA Yidan, YAN Jiaqing, CHU Shifeng, ZHANG Zhao, LIU Yangbo, CHEN Naihong, PENG Can. Mechanism of activation of NLRP3 inflammasome by α-synuclein performed fibrils[J]. Chinese Journal of Pharmacovigilance, 2023, 20(4): 409-415.

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Mechanism of activation of NLRP3 inflammasome by α-synuclein performed fibrils

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