open access

Vol 83, No 1 (2024): Folia Morphologica
Original article
Submitted: 2023-02-17
Accepted: 2023-04-12
Published online: 2023-05-08
Get Citation

Autophagy exerts a protective role in cervical spinal cord injury by microglia inhibition through the nuclear factor kappa-B pathway

Baicheng Yang1, Xinming Yang2
·
Pubmed: 37183514
·
Folia Morphol 2024;83(1):113-124.
Affiliations
  1. Hebei North University, Zhangjiakou, Hebei, China
  2. Department of Orthopaedics, the First Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei, China

open access

Vol 83, No 1 (2024): Folia Morphologica
ORIGINAL ARTICLES
Submitted: 2023-02-17
Accepted: 2023-04-12
Published online: 2023-05-08

Abstract

Background: Spinal cord injury (SCI) is a serious trauma to the central nervous system. M1/M2 microglial polarization as well as the following neuroinflammatory response are crucial factors in SCI. Autophagy plays an important role in SCI, but its neuroprotective or neurodegenerative role remains controversial. Materials and methods: Here, we majorly examined the properties of autophagy in SCI and uncovered the regulatory relationship between autophagy and microglial polarization in SCI. Results: In our study, the Basso-Beattie-Bresnahan (BBB) score was declined in SCI. The cervical contusion SCI stimulated a sustaining neuropathic pain-linked phenotype characterized by thermal hyperalgesia as well as mechanical allodynia. It was revealed the structural damage to the spinal cord in SCI. Besides, the expression of microglia markers as well as inflammatory factor were promoted in SCI. Cervical contusion SCI induced autophagy inhibition and nuclear factor kappa-B (NF-κB) activation in mice. More importantly, enhanced autophagy induced by rapamycin suppressed the NF-κB pathway and alleviated cervical contusion SCI-induced neurological function damage in mice. Additionally, rapamycin promoted microglia M2 polarization and improved microglia-mediated inflammatory response. Conclusions: In conclusion, our study demonstrated that autophagy played a protective role in cervical SCI by promoting microglia polarization toward M2 through the NF-κB pathway. Our study may provide a novel sight for SCI treatment.

Abstract

Background: Spinal cord injury (SCI) is a serious trauma to the central nervous system. M1/M2 microglial polarization as well as the following neuroinflammatory response are crucial factors in SCI. Autophagy plays an important role in SCI, but its neuroprotective or neurodegenerative role remains controversial. Materials and methods: Here, we majorly examined the properties of autophagy in SCI and uncovered the regulatory relationship between autophagy and microglial polarization in SCI. Results: In our study, the Basso-Beattie-Bresnahan (BBB) score was declined in SCI. The cervical contusion SCI stimulated a sustaining neuropathic pain-linked phenotype characterized by thermal hyperalgesia as well as mechanical allodynia. It was revealed the structural damage to the spinal cord in SCI. Besides, the expression of microglia markers as well as inflammatory factor were promoted in SCI. Cervical contusion SCI induced autophagy inhibition and nuclear factor kappa-B (NF-κB) activation in mice. More importantly, enhanced autophagy induced by rapamycin suppressed the NF-κB pathway and alleviated cervical contusion SCI-induced neurological function damage in mice. Additionally, rapamycin promoted microglia M2 polarization and improved microglia-mediated inflammatory response. Conclusions: In conclusion, our study demonstrated that autophagy played a protective role in cervical SCI by promoting microglia polarization toward M2 through the NF-κB pathway. Our study may provide a novel sight for SCI treatment.

Get Citation

Keywords

spinal cord injury, microglia activation, NF-κB, autophagy

About this article
Title

Autophagy exerts a protective role in cervical spinal cord injury by microglia inhibition through the nuclear factor kappa-B pathway

Journal

Folia Morphologica

Issue

Vol 83, No 1 (2024): Folia Morphologica

Article type

Original article

Pages

113-124

Published online

2023-05-08

Page views

697

Article views/downloads

489

DOI

10.5603/FM.a2023.0036

Pubmed

37183514

Bibliographic record

Folia Morphol 2024;83(1):113-124.

Keywords

spinal cord injury
microglia activation
NF-κB
autophagy

Authors

Baicheng Yang
Xinming Yang

References (44)
  1. Anjum A, Yazid MD, Fauzi Daud M, et al. Spinal cord injury: pathophysiology, multimolecular interactions, and underlying recovery mechanisms. Int J Mol Sci. 2020; 21(20).
  2. Chen S, Ye J, Chen X, et al. Valproic acid attenuates traumatic spinal cord injury-induced inflammation via STAT1 and NF-κB pathway dependent of HDAC3. J Neuroinflammation. 2018; 15(1): 150.
  3. Ding HL, Chen JL, Su S, et al. BDNF promotes activation of astrocytes and microglia contributing to neuroinflammation and mechanical allodynia in cyclophosphamide-induced cystitis. J Neuroinflammation. 2020; 17(19): e1166.
  4. Eli I, Lerner DP, Ghogawala Z. Acute traumatic spinal cord injury. Neurol Clin. 2021; 39(2): 471–488.
  5. Fan L, Liu C, Chen X, et al. Exosomes-Loaded electroconductive hydrogel synergistically promotes tissue repair after spinal cord injury via immunoregulation and enhancement of myelinated axon growth. Adv Sci (Weinh). 2022; 9(13): e2105586.
  6. Gao G, Chen W, Yan M, et al. Rapamycin regulates the balance between cardiomyocyte apoptosis and autophagy in chronic heart failure by inhibiting mTOR signaling. Int J Mol Med. 2020; 45(1): 195–209.
  7. Gao J, Sun Z, Xiao Z, et al. Dexmedetomidine modulates neuroinflammation and improves outcome via alpha2-adrenergic receptor signaling after rat spinal cord injury. Br J Anaesth. 2019; 123(6): 827–838.
  8. Gaojian T, Dingfei Q, Linwei Li, et al. Parthenolide promotes the repair of spinal cord injury by modulating M1/M2 polarization via the NF-κB and STAT 1/3 signaling pathway. Cell Death Discov. 2020; 6(1): 97.
  9. Gholaminejhad M, Jameie SB, Abdi M, et al. All-trans retinoic acid-preconditioned mesenchymal stem cells improve motor function and alleviate tissue damage after spinal cord injury by inhibition of Hmgb1/Nf-Κb/Nlrp3 pathway through autophagy activation. J Mol Neurosci. 2022; 72(5): 947–962.
  10. Gonzalez-Rothi EJ, Lee KZ. Intermittent hypoxia and respiratory recovery in pre-clinical rodent models of incomplete cervical spinal cord injury. Exp Neurol. 2021; 342: 113751.
  11. Hou Y, Luan J, Deng T, et al. Tauroursodeoxycholic acid alleviates secondary injury in spinal cord injury mice through reducing oxidative stress, apoptosis, and inflammatory response. J Neuroinflammation. 2021; 18: 216.
  12. Ji J, Xue TF, Guo XD, et al. Antagonizing peroxisome proliferator-activated receptor γ facilitates M1-to-M2 shift of microglia by enhancing autophagy via the LKB1-AMPK signaling pathway. Aging Cell. 2018; 17: e12774.
  13. Jiang P, Mizushima N. LC3- and p62-based biochemical methods for the analysis of autophagy progression in mammalian cells. Methods. 2015; 75: 13–18.
  14. Khan NZ, Cao T, He J, et al. Spinal cord injury alters microRNA and CD81+ exosome levels in plasma extracellular nanoparticles with neuroinflammatory potential. Brain Behav Immun. 2021; 92: 165–183.
  15. Klionsky D, Petroni G, Amaravadi R, et al. Autophagy in major human diseases. EMBO J. 2021; 40(19).
  16. Kwiecien JM, Dabrowski W, Dąbrowska-Bouta B, et al. Prolonged inflammation leads to ongoing damage after spinal cord injury. PLoS One. 2020; 15(3): e0226584.
  17. Lee SY, Schmit BD, Kurpad SN, et al. Acute magnetic resonance imaging predictors of chronic motor function and tissue sparing in rat cervical spinal cord injury. J Neurotrauma. 2022; 39(23-24): 1727–1740.
  18. Levine B, Kroemer G. Biological functions of autophagy genes: a disease perspective. Cell. 2019; 176(1-2): 11–42.
  19. Li Yi, He X, Kawaguchi R, et al. Microglia-organized scar-free spinal cord repair in neonatal mice. Nature. 2020; 587(7835): 613–618.
  20. Li Y, Lei Z, Ritzel RM, et al. Impairment of autophagy after spinal cord injury potentiates neuroinflammation and motor function deficit in mice. Theranostics. 2022; 12(12): 5364–5388.
  21. Li Y, Ritzel RM, Khan N, et al. Delayed microglial depletion after spinal cord injury reduces chronic inflammation and neurodegeneration in the brain and improves neurological recovery in male mice. Theranostics. 2020; 10(25): 11376–11403.
  22. Liu G, Fan G, Guo G, et al. FK506 attenuates the inflammation in rat spinal cord injury by inhibiting the activation of NF-κB in microglia cells. Cell Mol Neurobiol. 2017; 37(5): 843–855.
  23. Liu H, Zhang J, Xu X, et al. SARM1 promotes neuroinflammation and inhibits neural regeneration after spinal cord injury through NF-κB signaling. Theranostics. 2021; 11(9): 4187–4206.
  24. Liu J, Li R, Huang Z, et al. Rapamycin preserves neural tissue, promotes schwann cell myelination and reduces glial scar formation after hemi-contusion spinal cord injury in mice. Front Mol Neurosci. 2020; 13: 574041.
  25. Liu LR, Liu JC, Bao JS, et al. Interaction of microglia and astrocytes in the neurovascular unit. Front Immunol. 2020; 11: 1024.
  26. Liu W, Rong Y, Wang J, et al. Exosome-shuttled miR-216a-5p from hypoxic preconditioned mesenchymal stem cells repair traumatic spinal cord injury by shifting microglial M1/M2 polarization. J Neuroinflammation. 2020; 17(1): 47.
  27. Liu Z, Yao X, Jiang W, et al. Advanced oxidation protein products induce microglia-mediated neuroinflammation via MAPKs-NF-κB signaling pathway and pyroptosis after secondary spinal cord injury. J Neuroinflammation. 2020; 17(1): 90.
  28. Luo C, Tao L. The function and mechanisms of autophagy in spinal cord injury. Adv Exp Med Biol. 2020; 1207: 649–654.
  29. Mulero MC, Huxford T, Ghosh G. NF-κB, IκB, and IKK: integral components of immune system signaling. Adv Exp Med Biol. 2019; 1172: 207–226.
  30. Ray SK. Modulation of autophagy for neuroprotection and functional recovery in traumatic spinal cord injury. Neural Regen Res. 2020; 15(9): 1601–1612.
  31. Ren C, Han X, Lu C, et al. Ubiquitination of NF-κB p65 by FBXW2 suppresses breast cancer stemness, tumorigenesis, and paclitaxel resistance. Cell Death Differ. 2022; 29(2): 381–392.
  32. Rong Y, Liu W, Wang J, et al. Neural stem cell-derived small extracellular vesicles attenuate apoptosis and neuroinflammation after traumatic spinal cord injury by activating autophagy. Cell Death Dis. 2019; 10(5): 340.
  33. Shi Q, Wu Y, Zhang B, et al. Progranulin promotes functional recovery in rats with acute spinal cord injury via autophagy-induced anti-inflammatory microglial polarization. Mol Neurobiol. 2022; 59(7): 4304–4314.
  34. Sweeney MD, Zhao Z, Montagne A, et al. Blood-Brain barrier: from physiology to disease and back. Physiol Rev. 2019; 99(1): 21–78.
  35. Watson JL, Hala TJ, Putatunda R, et al. Persistent at-level thermal hyperalgesia and tactile allodynia accompany chronic neuronal and astrocyte activation in superficial dorsal horn following mouse cervical contusion spinal cord injury. PLoS One. 2014; 9(9): e109099.
  36. Wu C, Chen H, Zhuang R, et al. Betulinic acid inhibits pyroptosis in spinal cord injury by augmenting autophagy via the AMPK-mTOR-TFEB signaling pathway. Int J Biol Sci. 2021; 17(4): 1138–1152.
  37. Wu H, Zheng J, Xu S, et al. Mer regulates microglial M1/M2 polarization and alleviates neuroinflammation following traumatic brain injury. J Neuroinflammation. 2021; 18: 2.
  38. Xu Bo, Zhang Ws, Yang Jl, et al. Dexmedetomidine blocks thermal hyperalgesia and spinal glial activation in rat model of monoarthritis. Acta Pharmacol Sin. 2010; 31(5): 523–530.
  39. Xu S, Shao M, Ma X, et al. CD73 alleviates GSDMD-mediated pyroptosis in spinal cord injury through PI3K/AKT/Foxo1 signaling. Clin Transl Med. 2021; 11: e269.
  40. Zeng H, Liu N, Yang YY, et al. Lentivirus-mediated downregulation of α-synuclein reduces neuroinflammation and promotes functional recovery in rats with spinal cord injury. J Neuroinflammation. 2019; 16(1): 283.
  41. Zeng Z, Zhang Y, Jiang W, et al. Modulation of autophagy in traumatic brain injury. J Cell Physiol. 2020; 235(3): 1973–1985.
  42. Zhang Y, Liu D, Hu H, et al. HIF-1α/BNIP3 signaling pathway-induced-autophagy plays protective role during myocardial ischemia-reperfusion injury. Biomed Pharmacother. 2019; 120: 109464.
  43. Zhao H, Chen S, Gao K, et al. Resveratrol protects against spinal cord injury by activating autophagy and inhibiting apoptosis mediated by the SIRT1/AMPK signaling pathway. Neuroscience. 2017; 348: 241–251.
  44. Zhou K, Zheng Z, Li Y, et al. TFE3, a potential therapeutic target for spinal cord injury via augmenting autophagy flux and alleviating ER stress. Theranostics. 2020; 10(20): 9280–9302.

Regulations

Important: This website uses cookies. More >>

The cookies allow us to identify your computer and find out details about your last visit. They remembering whether you've visited the site before, so that you remain logged in - or to help us work out how many new website visitors we get each month. Most internet browsers accept cookies automatically, but you can change the settings of your browser to erase cookies or prevent automatic acceptance if you prefer.

By VM Media Group sp. z o.o., Grupa Via Medica, Świętokrzyska 73, 80–180 Gdańsk, Poland

tel.: +48 58 320 94 94, faks: +48 58 320 94 60, e-mail: viamedica@viamedica.pl