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Original Research | Open Access

GsMTx4 ameliorates spinal cord injury by regulating microglial polarization through the Piezo1/NFκB/STAT6 pathway

Weiwei Zhenga,1, Peng Zhanga,1, Hui Cheb,1, Yu Zhanga, Xing Yangb( ), Yixin Shena( )
Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou 215000, Jiangsu, China
Department of Orthopedics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou 215000, Jiangsu, China

1 These authors contributed equally to this work.

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Abstract

Background

Inflammatory reactions are recognized as pivotal in spinal cord injury (SCI), with the anti-inflammatory role of polarized microglia crucial in mitigating such injury. The present study aimed to determine the protective effects of GsMTx4 on functional recovery in a mouse model of SCI and investigate the role of GsMTx4 in cytokine-induced microglial activation and associated molecular mechanisms.

Methods

We assessed the effects of GsMTx4 on motor function in a mouse model of SCI, including neuronal survival and activated microglia in the vicinity of the injury after SCI. We also investigated the effects of GsMTx4 on expression of relevant inflammatory factors involved in cytokine-induced microglial activation and the associated signaling pathways.

Results

GsMTx4 effectively promoted functional recovery in mice and alleviated nerve damage after SCI. Additionally, GsMTx4 facilitated the transition of microglia from the M1 phenotype to the M2 phenotype, suppressed microglial activation, and reduced the expression of corresponding inflammatory mediators. These effects may involve modulation of neurogenic inflammation through the Piezo1/NFκB/STAT6 pathway, at least in part.

Conclusion

GsMTx4 safeguards against SCI by regulating microglial polarization, potentially via the Piezo1/NFκB/STAT6 pathway, offering initial evidence supporting the potential therapeutic efficacy of GsMTx4 for treatment of SCI.

Keywords

GsMTx4Spinal cord injuryMicrogliaPiezo1Neurogenic inflammation

References

1

Fyfe I. Regrowth and recovery in mice with spinal cord injury. Nat Rev Neurol. 2023;19(11):637. https://doi.org/10.1038/s41582-023-00890-3.
Crossref Google Scholar
2

Ding WZ, Hu SA, Wang PJ, et al. Spinal cord injury: the global incidence, prevalence, and disability from the global burden of disease study 2019. Spine. 2022;47(21):1532–1540. https://doi.org/10.1097/brs.0000000000004417.
Crossref Google Scholar
3

Huang HY, Sharma HS, Chen L, et al. Review of clinical neurorestorative strategies for spinal cord injury: exploring history and latest progresses. J Neurorestoratol. 2018;6(1):171–178. https://doi.org/10.26599/jnr.2018.9040013.
Crossref Google Scholar
4

Dalle DU, Sriram S, Bandyopadhyay S, et al. Management and outcomes of traumatic pediatric spinal cord injuries in low- and middle-income countries: a scoping review. World Neurosurg. 2022;165:180-187.e3. https://doi.org/10.1016/j.wneu.2022.06.030.
Crossref Google Scholar
5

Ma QP, Woolf CJ. Progressive tactile hypersensitivity: an inflammation-induced incremental increase in the excitability of the spinal cord. Pain. 1996;67(1):97–106. https://doi.org/10.1016/0304-3959(96)03105-3.
Crossref Google Scholar
6

Kroner A, Greenhalgh A, Zarruk J, et al. TNF and increased intracellular iron alter macrophage polarization to a detrimental M1 phenotype in the injured spinal cord. Neuron. 2014;83(5):1098–1116. https://doi.org/10.1016/j.neuron.2014.07.027.
Crossref Google Scholar
7

Zhao JH, Li Q, Ouyang XT, et al. The effect of CX3CL1/CX3CR1 signal axis on microglia in central nervous system diseases. J Neurorestoratol. 2023;11(1):100042. https://doi.org/10.1016/j.jnrt.2023.100042.
Crossref Google Scholar
8

Inoue S, Li CX, Hatakeyama J, et al. Higher-intensity ultrasound accelerates fracture healing via mechanosensitive ion channel Piezo1. Bone. 2023;177:116916. https://doi.org/10.1016/j.bone.2023.116916.
Crossref Google Scholar
9

Ren X, Zhuang H, Li B, et al. Gsmtx4 alleviated osteoarthritis through Piezo1/calcineurin/NFAT1 signaling axis under excessive mechanical strain. Int J Mol Sci. 2023;24(4):4022. https://doi.org/10.3390/ijms24044022.
Crossref Google Scholar
10

Ihara T, Mitsui T, Shimura H, et al. Different effects of GsMTx4 on nocturia associated with the circadian clock and Piezo1 expression in mice. Life Sci. 2021;278:119555. https://doi.org/10.1016/j.lfs.2021.119555.
Crossref Google Scholar
11

Velasco-Estevez M, Rolle SO, Mampay M, et al. Piezo1 regulates calcium oscillations and cytokine release from astrocytes. Glia. 2020;68(1):145–160. https://doi.org/10.1002/glia.23709.
Crossref Google Scholar
12

Velasco-Estevez M, Gadalla KKE, Linan-Barba N, et al. Inhibition of Piezo1 attenuates demyelination in the central nervous system. Glia. 2020;68(2):356–375. https://doi.org/10.1002/glia.23722.
Crossref Google Scholar
13

Bryniarska-Kubiak N, Kubiak A, Basta-Kaim A. Mechanotransductive receptor Piezo1 as a promising target in the treatment of neurological diseases. Curr Neuropharmacol. 2023;21(10):2030–2035. https://doi.org/10.2174/1570159X20666220927103454.
Crossref Google Scholar
14

Velasco-Estevez M, Koch N, Klejbor I, et al. Mechanoreceptor Piezo1 is downregulated in multiple sclerosis brain and is involved in the maturation and migration of oligodendrocytes in vitro. Front Cell Neurosci. 2022;16:914985. https://doi.org/10.3389/fncel.2022.914985.
Crossref Google Scholar
15

Johnson JAG, Liu HX, Hoger U, et al. Mechanotransduction channel Piezo is widely expressed in the spider, Cupiennius salei, mechanosensory neurons and central nervous system. Sci Rep. 2021;11(1):7994. https://doi.org/10.1038/s41598-021-87202-1.
Crossref Google Scholar
16
Wu XB, Liu JY, Li W, et al. CD1d-dependent neuroinflammation impairs tissue repair and functional recovery following a spinal cord injury. bioRxiv. 2023. https://doi.org/10.1101/2023.10.13.562047, 2023.10.13.562047.
Crossref
17

Blumenthal NR, Hermanson O, Heimrich B, et al. Stochastic nanoroughness modulates neuron-astrocyte interactions and function via mechanosensing cation channels. Proc Natl Acad Sci U S A. 2014;111(45):16124–16129. https://doi.org/10.1073/pnas.1412740111.
Crossref Google Scholar
18

Liu K, Lu Y, Lee JK, et al. PTEN deletion enhances the regenerative ability of adult corticospinal neurons. Nat Neurosci. 2010;13(9):1075–1081. https://doi.org/10.1038/nn.2603.
Crossref Google Scholar
19

Yoshizaki S, Yokota K, Kubota K, et al. The beneficial aspects of spasticity in relation to ambulatory ability in mice with spinal cord injury. Spinal Cord. 2020;58(5):537–543. https://doi.org/10.1038/s41393-019-0395-9.
Crossref Google Scholar
20

Basso DM, Fisher LC, Anderson AJ, et al. Basso Mouse Scale for locomotion detects differences in recovery after spinal cord injury in five common mouse strains. J Neurotrauma. 2006;23(5):635–659. https://doi.org/10.1089/neu.2006.23.635.
Crossref Google Scholar
21

Liu C, Xia YN, Fu SC, et al. Inhibition of Piezo1 ameliorates intestinal inflammation and limits the activation of group 3 innate lymphoid cells in experimental colitis. J Innate Immun. 2023;15(1):709–723. https://doi.org/10.1159/000533525.
Crossref Google Scholar
22

Rong ZJ, Cai HH, Wang H, et al. Ursolic acid ameliorates spinal cord injury in mice by regulating gut microbiota and metabolic changes. Front Cell Neurosci. 2022;16:872935. https://doi.org/10.3389/fncel.2022.872935.
Crossref Google Scholar
23

Jafari A, Khalatbary AR, Taghiloo S, et al. Exosomes derived from human placental mesenchymal stem cells in combination with hyperbaric oxygen synergically alleviates spinal cord ischemia-reperfusion injury. Regen Ther. 2023;24:407–416. https://doi.org/10.1016/j.reth.2023.09.003.
Crossref Google Scholar
24

Atcha H, Jairaman A, Holt JR, et al. Mechanically activated ion channel Piezo1 modulates macrophage polarization and stiffness sensing. Nat Commun. 2021;12(1):3256. https://doi.org/10.1038/s41467-021-23482-5.
Crossref Google Scholar
25

He Y, Deng B, Liu SL, et al. Myeloid Piezo1 deletion protects renal fibrosis by restraining macrophage infiltration and activation. Hypertension. 2022;79(5):918–931. https://doi.org/10.1161/hypertensionaha.121.18750.
Crossref Google Scholar
26

Solis AG, Bielecki P, Steach HR, et al. Mechanosensation of cyclical force by PIEZO1 is essential for innate immunity. Nature. 2019;573(7772):69–74. https://doi.org/10.1038/s41586-019-1485-8.
Crossref Google Scholar
27

Zhang M, Malko P, Jiang LH. Mechanosensitive Piezo1 channel regulation of microglial cell function and implications to neurodegenerative diseases and neuroinflammation. Neural Regen Res. 2023;18(11):2385–2386. https://doi.org/10.4103/1673-5374.371355.
Crossref Google Scholar
28

Li Y, He XL, Kawaguchi R, et al. Microglia-organized scar-free spinal cord repair in neonatal mice. Nature. 2020;587(7835):613–618. https://doi.org/10.1038/s41586-020-2795-6.
Crossref Google Scholar
29

Zhao WY, Gasterich N, Clarner T, et al. Astrocytic Nrf2 expression protects spinal cord from oxidative stress following spinal cord injury in a male mouse model. J Neuroinflammation. 2022;19(1):134. https://doi.org/10.1186/s12974-022-02491-1.
Crossref Google Scholar
30

Chen TB, He XQ, Wang J, et al. NT-3 combined with TGF-β signaling pathway enhance the repair of spinal cord injury by inhibiting glial scar formation and promoting axonal regeneration. Mol Biotechnol. 2024;66(6):1484–1495. https://doi.org/10.1007/s12033-023-00781-4.
Crossref Google Scholar
31

Duan H, Pang Y, Zhao C, et al. A novel, minimally invasive technique to establish the animal model of spinal cord injury. Ann Transl Med. 2021;9(10):881. https://doi.org/10.21037/atm-21-2063.
Crossref Google Scholar
32

Timotius IK, Bieler L, Couillard-Despres S, et al. Combination of defined CatWalk gait parameters for predictive locomotion recovery in experimental spinal cord injury rat models. eNeuro. 2021;8(2):ENEURO.0497-ENEURO.0420.2021. https://doi.org/10.1523/ENEURO.0497-20.2021.
Crossref Google Scholar
33

Jiang ZF, Zeng Z, He H, et al. Lycium barbarum glycopeptide alleviates neuroinflammation in spinal cord injury via modulating docosahexaenoic acid to inhibiting MAPKs/NF-kB and pyroptosis pathways. J Transl Med. 2023;21(1):770. https://doi.org/10.1186/s12967-023-04648-9.
Crossref Google Scholar
34

Gu CJ, Geng XW, Wu YC, et al. Engineered macrophage Membrane-Coated nanoparticles with enhanced CCR2 expression promote spinal cord injury repair by suppressing neuroinflammation and neuronal death. Small. 2024;20(10):2305659. https://doi.org/10.1002/smll.202305659.
Crossref Google Scholar
35

Li YL, Fan H, Han X, et al. Long non-coding RNA MALAT1 protects against spinal cord injury via suppressing microRNA-125b-5p mediated microglial M1 polarization, neuroinflammation, and neural apoptosis. Mol Neurobiol. 2024;61(4):2136–2150. https://doi.org/10.1007/s12035-023-03664-6.
Crossref Google Scholar
36

Li JL, Fu GQ, Wang YY, et al. The polarization of microglia and infiltrated macrophages in the injured mice spinal cords: a dynamic analysis. PeerJ. 2023;11:e14929. https://doi.org/10.7717/peerj.14929.
Crossref Google Scholar
37

Gao ZS, Zhang CJ, Xia N, et al. Berberine-loaded M2 macrophage-derived exosomes for spinal cord injury therapy. Acta Biomater. 2021;126:211–223. https://doi.org/10.1016/j.actbio.2021.03.018.
Crossref Google Scholar
38

Jin Y, Li J, Wang YT, et al. Functional role of mechanosensitive ion channel Piezo1 in human periodontal ligament cells. Angle Orthod. 2015;85(1):87–94. https://doi.org/10.2319/123113-955.1.
Crossref Google Scholar
Journal of Neurorestoratology
Volume 12 Issue 4,
December 2024
Article number: 100144
DOI: 10.1016/j.jnrt.2024.100144
Cite this article:
Zheng W, Zhang P, Che H, et al. GsMTx4 ameliorates spinal cord injury by regulating microglial polarization through the Piezo1/NFκB/STAT6 pathway. Journal of Neurorestoratology, 2024, 12(4): 100144. https://doi.org/10.1016/j.jnrt.2024.100144

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Received: 29 December 2023
Revised: 04 April 2024
Accepted: 05 July 2024
Published: 16 August 2024
© 2024 The Authors.

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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