Chen LP, Gui XD, Tian WD, Kan HM, Huang JZ, Ji FH. Botulinum toxin type A-targeted SPP1 contributes to neuropathic pain by the activation of microglia pyroptosis. World J Psychiatry 2024; 14(8): 1254-1266 [DOI: 10.5498/wjp.v14.i8.1254]
Corresponding Author of This Article
Fu-Hai Ji, MD, Professor, Department of Anesthesiology, The First Affiliated Hospital of Soochow University, No. 899 Pinghai Road, Suzhou 215006, Jiangsu Province, China. jifuhai@suda.edu.cn
Research Domain of This Article
Neurosciences
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Li-Ping Chen, Fu-Hai Ji, Department of Anesthesiology, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu Province, China
Xiao-Die Gui, Wen-Di Tian, Jin-Zhao Huang, Department of Pain, Xuzhou Medical University, Xuzhou 221004, Jiangsu Province, China
Hou-Ming Kan, Faculty of Medicine, Macao University of Science and Technology, Macau 999078, China
Author contributions: Chen LP and Ji FH designed the research study; Chen LP, Gui XD, and Tian WD performed the research; Chen LP, Kan HM, and Huang JZ analyzed the data; Chen LP and Ji FH wrote the manuscript. All authors have read and approved the final manuscript.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Xuzhou Medical University (No. SC225179).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Fu-Hai Ji, MD, Professor, Department of Anesthesiology, The First Affiliated Hospital of Soochow University, No. 899 Pinghai Road, Suzhou 215006, Jiangsu Province, China. jifuhai@suda.edu.cn
Received: April 3, 2024 Revised: May 29, 2024 Accepted: July 2, 2024 Published online: August 19, 2024 Processing time: 130 Days and 18.4 Hours
Abstract
BACKGROUND
Neuropathic pain (NP) is the primary symptom of various neurological conditions. Patients with NP often experience mood disorders, particularly depression and anxiety, that can severely affect their normal lives. Microglial cells are associated with NP. Excessive inflammatory responses, especially the secretion of large amounts of pro-inflammatory cytokines, ultimately lead to neuroinflammation. Microglial pyroptosis is a newly discovered form of inflammatory cell death associated with immune responses and inflammation-related diseases of the central nervous system.
AIM
To investigate the effects of botulinum toxin type A (BTX-A) on microglial pyroptosis in terms of NP and associated mechanisms.
METHODS
Two models, an in vitro lipopolysaccharide (LPS)-stimulated microglial cell model and a selective nerve injury model using BTX-A and SPP1 knockdown treatments, were used. Key proteins in the pyroptosis signaling pathway, NLRP3-GSDMD, were assessed using western blotting, real-time quantitative polymerase chain reaction, and immunofluorescence. Inflammatory factors [interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α] were assessed using enzyme-linked immunosorbent assay. We also evaluated microglial cell proliferation and apoptosis. Furthermore, we measured pain sensation by assessing the delayed hind paw withdrawal latency using thermal stimulation.
RESULTS
The expression levels of ACS and GSDMD-N and the mRNA expression of TNF-α, IL-6, and IL-1β were enhanced in LPS-treated microglia. Furthermore, SPP1 expression was also induced in LPS-treated microglia. Notably, BTX-A inhibited SPP1 mRNA and protein expression in the LPS-treated microglia. Additionally, depletion of SPP1 or BTX-A inhibited cell viability and induced apoptosis in LPS-treated microglia, whereas co-treatment with BTX-A enhanced the effect of SPP1 short hairpin (sh)RNA in LPS-treated microglia. Finally, SPP1 depletion or BTX-A treatment reduced the levels of GSDMD-N, NLPRP3, and ASC and suppressed the production of inflammatory factors.
CONCLUSION
Notably, BTX-A therapy and SPP1 shRNA enhance microglial proliferation and apoptosis and inhibit microglial death. It improves pain perception and inhibits microglial activation in rats with selective nerve pain.
Core Tip: Neuropathic pain (NP) arises from structural lesions that induce functional abnormalities in the central and peripheral nervous systems. This condition plagues approximately 10% of the population. In this study, we found that microglial pyroptosis was closely correlated with NP progression and that botulinum toxin type A (BTX-A) treatment notably alleviated this. Our mechanistic study identified that SPP1 may be positively correlated with microglial pyroptosis and inflammation during NP and that it is targeted by BTX-A. These findings provide novel evidence for the application of BTX-A in the treatment of NP.
