Iron induces B cell pyroptosis through Tom20–Bax–caspase–gasdermin E signaling to promote inflammation post-spinal cord injury
-
Published:2023-07-22
Issue:1
Volume:20
Page:
-
ISSN:1742-2094
-
Container-title:Journal of Neuroinflammation
-
language:en
-
Short-container-title:J Neuroinflammation
Author:
Wu Chengjie,Wang Lining,Chen Sixian,Shi Lei,Liu Mengmin,Tu Pengcheng,Sun Jie,Zhao Ruihua,Zhang Yafeng,Wang Jianwei,Pan Yalan,Ma Yong,Guo Yang
Abstract
Abstract
Background
Immune inflammatory responses play an important role in spinal cord injury (SCI); however, the beneficial and detrimental effects remain controversial. Many studies have described the role of neutrophils, macrophages, and T lymphocytes in immune inflammatory responses after SCI, although little is known about the role of B lymphocytes, and immunosuppression can easily occur after SCI.
Methods
A mouse model of SCI was established, and HE staining and Nissl staining were performed to observe the pathological changes. The size and morphology of the spleen were examined, and the effects of SCI on spleen function and B cell levels were detected by flow cytometry and ELISA. To explore the specific mechanism of immunosuppression after SCI, B cells from the spleens of SCI model mice were isolated using magnetic beads and analyzed by 4D label-free quantitative proteomics. The level of inflammatory cytokines and iron ions were measured, and the expression of proteins related to the Tom20 pathway was quantified by western blotting. To clarify the relationship between iron ions and B cell pyroptosis after SCI, we used FeSO4 and CCCP, which induce oxidative stress to stimulate SCI, to interfere with B cell processes. siRNA transfection to knock down Tom20 (Tom20-KD) in B cells and human B lymphocytoma cell was used to verify the key role of Tom20. To further explore the effect of iron ions on SCI, we used deferoxamine (DFO) and iron dextran (ID) to interfere with SCI processes in mice. The level of iron ions in splenic B cells and the expression of proteins related to the Tom20–Bax–caspase–gasdermin E (GSDME) pathway were analyzed.
Results
SCI could damage spleen function and lead to a decrease in B cell levels; SCI upregulated the expression of Tom20 protein in the mitochondria of B cells; SCI could regulate the concentration of iron ions and activate the Tom20–Bax–caspase–GSDME pathway to induce B cell pyroptosis. Iron ions aggravated CCCP-induced B cell pyroptosis and human B lymphocytoma pyroptosis by activating the Tom20–Bax–caspase–GSDME pathway. DFO could reduce inflammation and promote repair after SCI by inhibiting Tom20–Bax–caspase–GSDME-induced B cell pyroptosis.
Conclusions
Iron overload activates the Tom20–Bax–caspase–GSDME pathway after SCI, induces B cell pyroptosis, promotes inflammation, and aggravates the changes caused by SCI. This may represent a novel mechanism through which the immune inflammatory response is induced after SCI and may provide a new key target for the treatment of SCI.
Funder
2022 Jiangsu Province Graduate Research and Practice Innovation Project
Foundation of Jiangsu CM Clinical Innovation Center of Degenerative Bone & Joint Disease
the Jiangsu Province University Natural Science Foundation Project
National Natural Science Foundation of China
Traditional Chinese and Western Medicine Clinical Medicine Brand Construction Project of Jiangsu Higher Education Institutions
Natural Science Foundation Youth Project of Nanjing University of Chinese Medicine
Publisher
Springer Science and Business Media LLC
Subject
Cellular and Molecular Neuroscience,Neurology,Immunology,General Neuroscience
Reference45 articles.
1. Chan BC, Cadarette SM, Wodchis WP, Krahn MD, Mittmann N. The lifetime cost of spinal cord injury in Ontario, Canada: a population-based study from the perspective of the public health care payer. J Spinal Cord Med. 2019;42:184–93.
2. Orr MB, Gensel JC. Spinal cord injury scarring and inflammation: therapies targeting glial and inflammatory responses. Neurotherapeutics. 2018;15:541–53.
3. Ziegler G, Grabher P, Thompson A, Altmann D, Hupp M, Ashburner J, Friston K, Weiskopf N, Curt A, Freund P. Progressive neurodegeneration following spinal cord injury: implications for clinical trials. Neurology. 2018;90:e1257–66.
4. Anwar MA, Al Shehabi TS, Eid AH. Inflammogenesis of secondary spinal cord injury. Front Cell Neurosci. 2016;10:98.
5. Schwab JM, Zhang Y, Kopp MA, Brommer B, Popovich PG. The paradox of chronic neuroinflammation, systemic immune suppression, autoimmunity after traumatic chronic spinal cord injury. Exp Neurol. 2014;258:121–9.
Cited by
1 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献
1. Tumor iron homeostasis and immune regulation;Trends in Pharmacological Sciences;2024-02