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Photobiomodulation Increases M2-Type Polarization of Macrophages by Inhibiting Versican Production After Spinal Cord Injury

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Abstract

Spinal cord injury (SCI) is a catastrophic accidence with little effective treatment, and inflammation played an important role in that. Previous studies showed photobiomodulation (PBM) could effectively downregulate the process of inflammation with modification of macrophage polarization after SCI; however, the potential mechanism behind that is still unclear. In the presented study, we aimed to investigate the effect of PBM on the expression level of versican, a matrix molecular believed to be associated with inflammation, and tried to find the mechanism on how that could regulate the inflammation process. Using immunofluorescence technique and western blot, we found the expression level of versican is increased after injury and markedly downregulated by irradiation treatment. Using virus intrathecal injection, we found the knock-down of versican could produce the effect similar to that of PBM and might have an effect on inflammation and macrophage polarization after SCI. To further verify the deduction, we peptide the supernatant of astrocytes to induce M0, M1, and M2 macrophages. We found that the versican produced by astrocytes might have a role on the promotion of M2 macrophages to inflammatory polarization. Finally, we investigated the potential pathway in the regulation of M2 polarization with the induction of versican. This study tried to give an interpretation on the mechanism of inflammation inhibition for PBM in the perspective of matrix regulation. Our results might provide light on the inflammation regulation after SCI.

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Data Availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. (2019) Global, regional, and national burden of neurological disorders, 1990–2016: a systematic analysis for the global burden of disease study 2016. Lancet Neurol 18(5):459–80. https://doi.org/10.1016/s1474-4422(18)30499-x

  2. David S, Kroner A (2011) Repertoire of microglial and macrophage responses after spinal cord injury. Nat Rev Neurosci 12(7):388–399. https://doi.org/10.1038/nrn3053

    Article  CAS  PubMed  Google Scholar 

  3. Popovich PG, Longbrake EE (2008) Can the immune system be harnessed to repair the cns? Nat Rev Neurosci 9(6):481–493. https://doi.org/10.1038/nrn2398

    Article  CAS  PubMed  Google Scholar 

  4. O’Reilly ML, Tom VJ (2020) Neuroimmune system as a driving force for plasticity following cns injury. Front Cell Neurosci 14:187. https://doi.org/10.3389/fncel.2020.00187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Serhan CN (2014) Pro-resolving lipid mediators are leads for resolution physiology. Nature 510(7503):92–101. https://doi.org/10.1038/nature13479

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  6. Gensel JC, Zhang B (2015) Macrophage activation and its role in repair and pathology after spinal cord injury. Brain Res 1619:1–11. https://doi.org/10.1016/j.brainres.2014.12.045

    Article  CAS  PubMed  Google Scholar 

  7. Kong X, Gao J (2017) Macrophage polarization: a key event in the secondary phase of acute spinal cord injury. J Cell Mol Med 21(5):941–954. https://doi.org/10.1111/jcmm.13034

    Article  PubMed  Google Scholar 

  8. Kigerl KA, Gensel JC, Ankeny DP et al (2009) Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J Neurosci 29(43):13435–13444. https://doi.org/10.1523/jneurosci.3257-09.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Mussttaf RA, Jenkins DFL, Jha AN (2019) Assessing the impact of low level laser therapy (lllt) on biological systems: a review. Int J Radiat Biol 95(2):120–143. https://doi.org/10.1080/09553002.2019.1524944

    Article  CAS  PubMed  Google Scholar 

  10. Ma Y, Li P, Ju C et al (2022) Photobiomodulation attenuates neurotoxic polarization of macrophages by inhibiting the notch1-hif-1α/nf-κb signalling pathway in mice with spinal cord injury. Front Immunol 13:816952. https://doi.org/10.3389/fimmu.2022.816952

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Svobodova B, Kloudova A, Ruzicka J et al (2019) The effect of 808 nm and 905 nm wavelength light on recovery after spinal cord injury. Sci Rep 9(1):7660. https://doi.org/10.1038/s41598-019-44141-2

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  12. Song JW, Li K, Liang ZW et al (2017) Low-level laser facilitates alternatively activated macrophage/microglia polarization and promotes functional recovery after crush spinal cord injury in rats. Sci Rep 7(1):620. https://doi.org/10.1038/s41598-017-00553-6

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  13. Francos-Quijorna I, Sánchez-Petidier M, Burnside ER et al (2022) Chondroitin sulfate proteoglycans prevent immune cell phenotypic conversion and inflammation resolution via tlr4 in rodent models of spinal cord injury. Nat Commun 13(1):2933. https://doi.org/10.1038/s41467-022-30467-5

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bartus K, James ND, Didangelos A et al (2014) Large-scale chondroitin sulfate proteoglycan digestion with chondroitinase gene therapy leads to reduced pathology and modulates macrophage phenotype following spinal cord contusion injury. J Neurosci 34(14):4822–4836. https://doi.org/10.1523/jneurosci.4369-13.2014

    Article  PubMed  PubMed Central  Google Scholar 

  15. Dyck S, Kataria H, Alizadeh A et al (2018) Perturbing chondroitin sulfate proteoglycan signaling through lar and ptpσ receptors promotes a beneficial inflammatory response following spinal cord injury. J Neuroinflammation 15(1):90. https://doi.org/10.1186/s12974-018-1128-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wight TN, Kang I, Merrilees MJ (2014) Versican and the control of inflammation. Matrix Biol 35:152–161. https://doi.org/10.1016/j.matbio.2014.01.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wight TN, Kang I, Evanko SP et al (2020) Versican-a critical extracellular matrix regulator of immunity and inflammation. Front Immunol 11:512. https://doi.org/10.3389/fimmu.2020.00512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Patel M, Li Y, Anderson J et al (2021) Gsx1 promotes locomotor functional recovery after spinal cord injury. Mol Ther 29(8):2469–2482. https://doi.org/10.1016/j.ymthe.2021.04.027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zou Y, Zhang J, Xu J et al (2021) Sirt6 inhibition delays peripheral nerve recovery by suppressing migration, phagocytosis and m2-polarization of macrophages. Cell Biosci 11(1):210. https://doi.org/10.1186/s13578-021-00725-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Cai Y, Li J, Zhang Z et al (2017) Zbtb38 is a novel target for spinal cord injury. Oncotarget 8(28):45356–66. https://doi.org/10.18632/oncotarget.17487

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  22. Smith RR, Burke DA, Baldini AD et al (2006) The louisville swim scale: a novel assessment of hindlimb function following spinal cord injury in adult rats. J Neurotrauma 23(11):1654–1670. https://doi.org/10.1089/neu.2006.23.1654

    Article  PubMed  Google Scholar 

  23. Song Y, Yang C, Gao S et al (2014) Age-triggered and dark-induced leaf senescence require the bhlh transcription factors pif3, 4, and 5. Mol Plant 7(12):1776–1787. https://doi.org/10.1093/mp/ssu109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wolfes AC, Ahmed S, Awasthi A et al (2017) A novel method for culturing stellate astrocytes reveals spatially distinct ca2+ signaling and vesicle recycling in astrocytic processes. J Gen Physiol 149(1):149–170. https://doi.org/10.1085/jgp.201611607

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Chen W, Wang H, Zhu Z et al (2020) Exosome-shuttled circshoc2 from ipass regulates neuronal autophagy and ameliorates ischemic brain injury via the mir-7670-3p/sirt1 axis. Mol Ther Nucleic Acids 22:657–672. https://doi.org/10.1016/j.omtn.2020.09.027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zrzavy T, Schwaiger C, Wimmer I et al (2021) Acute and non-resolving inflammation associate with oxidative injury after human spinal cord injury. Brain 144(1):144–161. https://doi.org/10.1093/brain/awaa360

    Article  PubMed  Google Scholar 

  27. Greenhalgh AD, David S, Bennett FC (2020) Immune cell regulation of glia during cns injury and disease. Nat Rev Neurosci 21(3):139–152. https://doi.org/10.1038/s41583-020-0263-9

    Article  CAS  PubMed  Google Scholar 

  28. Rolls A, Shechter R, Schwartz M (2009) The bright side of the glial scar in cns repair. Nat Rev Neurosci 10(3):235–241. https://doi.org/10.1038/nrn2591

    Article  CAS  PubMed  Google Scholar 

  29. Sun J, Zhang J, Li K et al (2020) Photobiomodulation therapy inhibit the activation and secretory of astrocytes by altering macrophage polarization. Cell Mol Neurobiol 40(1):141–152. https://doi.org/10.1007/s10571-019-00728-x

    Article  CAS  PubMed  Google Scholar 

  30. de Brito SK, Rodrigues M, de Souza SD et al (2020) Differential expression of inflammatory and anti-inflammatory mediators by m1 and m2 macrophages after photobiomodulation with red or infrared lasers. Lasers Med Sci 35(2):337–343. https://doi.org/10.1007/s10103-019-02817-1

    Article  Google Scholar 

  31. Zheng Q, Zhang J, Zuo X et al (2021) Photobiomodulation promotes neuronal axon regeneration after oxidative stress and induces a change in polarization from m1 to m2 in macrophages via stimulation of ccl2 in neurons: relevance to spinal cord injury. J Mol Neurosci 71(6):1290–1300. https://doi.org/10.1007/s12031-020-01756-9

    Article  CAS  PubMed  Google Scholar 

  32. Palaga T, Buranaruk C, Rengpipat S et al (2008) Notch signaling is activated by tlr stimulation and regulates macrophage functions. Eur J Immunol 38(1):174–183. https://doi.org/10.1002/eji.200636999

    Article  CAS  PubMed  Google Scholar 

  33. Wight TN (2018) A role for proteoglycans in vascular disease. Matrix Biol 71–72:396–420. https://doi.org/10.1016/j.matbio.2018.02.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kang I, Chang MY, Wight TN et al (2018) Proteoglycans as immunomodulators of the innate immune response to lung infection. J Histochem Cytochem 66(4):241–259. https://doi.org/10.1369/0022155417751880

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Yan Y, Qin D, Hu B et al (2019) Deletion of mir-126a promotes hepatic aging and inflammation in a mouse model of cholestasis. Mol Ther Nucleic Acids 16:494–504. https://doi.org/10.1016/j.omtn.2019.04.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kunisada M, Yogianti F, Sakumi K et al (2011) Increased expression of versican in the inflammatory response to uvb- and reactive oxygen species-induced skin tumorigenesis. Am J Pathol 179(6):3056–3065. https://doi.org/10.1016/j.ajpath.2011.08.042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Tang PH, Velez G, Tsang SH et al (2019) Vcan canonical splice site mutation is associated with vitreoretinal degeneration and disrupts an mmp proteolytic site. Invest Ophthalmol Vis Sci 60(1):282–293. https://doi.org/10.1167/iovs.18-25624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Islam S, Chuensirikulchai K, Khummuang S et al (2020) Accumulation of versican facilitates wound healing: implication of its initial adamts-cleavage site. Matrix Biol 87:77–93. https://doi.org/10.1016/j.matbio.2019.10.006

    Article  CAS  PubMed  Google Scholar 

  39. Dours-Zimmermann MT, Maurer K, Rauch U et al (2009) Versican v2 assembles the extracellular matrix surrounding the nodes of ranvier in the cns. J Neurosci 29(24):7731–7742. https://doi.org/10.1523/jneurosci.4158-08.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Asher RA, Morgenstern DA, Shearer MC et al (2002) Versican is upregulated in cns injury and is a product of oligodendrocyte lineage cells. J Neurosci 22(6):2225–2236. https://doi.org/10.1523/jneurosci.22-06-02225.2002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Hu X, Leak RK, Shi Y et al (2015) Microglial and macrophage polarization—new prospects for brain repair. Nat Rev Neurol 11(1):56–64. https://doi.org/10.1038/nrneurol.2014.207

    Article  PubMed  Google Scholar 

  42. Liu ZJ, Ran YY, Qie SY et al (2019) Melatonin protects against ischemic stroke by modulating microglia/macrophage polarization toward anti-inflammatory phenotype through stat3 pathway. CNS Neurosci Ther 25(12):1353–1362. https://doi.org/10.1111/cns.13261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Yao XQ, Liu ZY, Chen JY et al (2021) Proteomics and bioinformatics reveal insights into neuroinflammation in the acute to subacute phases in rat models of spinal cord contusion injury. FASEB J 35(7):e21735. https://doi.org/10.1096/fj.202100081RR

    Article  CAS  PubMed  Google Scholar 

  44. Tran AP, Warren PM, Silver J (2018) The biology of regeneration failure and success after spinal cord injury. Physiol Rev 98(2):881–917. https://doi.org/10.1152/physrev.00017.2017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Bradbury EJ, Burnside ER (2019) Moving beyond the glial scar for spinal cord repair. Nat Commun 10(1):3879. https://doi.org/10.1038/s41467-019-11707-7

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  46. Eli I, Lerner DP, Ghogawala Z (2021) Acute traumatic spinal cord injury. Neurol Clin 39(2):471–488. https://doi.org/10.1016/j.ncl.2021.02.004

    Article  PubMed  Google Scholar 

  47. Fischer I, Dulin JN, Lane MA (2020) Transplanting neural progenitor cells to restore connectivity after spinal cord injury. Nat Rev Neurosci 21(7):366–383. https://doi.org/10.1038/s41583-020-0314-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Bellver-Landete V, Bretheau F, Mailhot B et al (2019) Microglia are an essential component of the neuroprotective scar that forms after spinal cord injury. Nat Commun 10(1):518. https://doi.org/10.1038/s41467-019-08446-0

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  49. Zhu Y, Soderblom C, Krishnan V et al (2015) Hematogenous macrophage depletion reduces the fibrotic scar and increases axonal growth after spinal cord injury. Neurobiol Dis 74:114–125. https://doi.org/10.1016/j.nbd.2014.10.024

    Article  CAS  PubMed  Google Scholar 

  50. Liu B, Gu Y, Pei S et al (2019) Interleukin-1 receptor associated kinase (irak)-m -mediated type 2 microglia polarization ameliorates the severity of experimental autoimmune encephalomyelitis (eae). J Autoimmun 102:77–88. https://doi.org/10.1016/j.jaut.2019.04.020

    Article  CAS  PubMed  Google Scholar 

  51. Caso JR, Pradillo JM, Hurtado O et al (2007) Toll-like receptor 4 is involved in brain damage and inflammation after experimental stroke. Circulation 115(12):1599–1608. https://doi.org/10.1161/circulationaha.106.603431

    Article  CAS  PubMed  Google Scholar 

  52. Ye Y, Jin T, Zhang X et al (2019) Meisoindigo protects against focal cerebral ischemia-reperfusion injury by inhibiting nlrp3 inflammasome activation and regulating microglia/macrophage polarization via tlr4/nf-κb signaling pathway. Front Cell Neurosci 13:553. https://doi.org/10.3389/fncel.2019.00553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Degboé Y, Poupot R, Poupot M (2022) Repolarization of unbalanced macrophages: Unmet medical need in chronic inflammation and cancer. Int J Mol Sci 23(3). https://doi.org/10.3390/ijms23031496

  54. Cutolo M, Soldano S, Contini P et al (2013) Intracellular nf-kb-decrease and ikbα increase in human macrophages following ctla4-ig treatment. Clin Exp Rheumatol 31(6):943–946

    PubMed  Google Scholar 

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Funding

This work was supported by the Natural Science Foundation of China (NO. 81070996, NO. 81572151) and Shaanxi Provincial Key R&D Program (NO. 2020ZDLSF02-05, NO. 2021ZDLSF02-10).

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Zhi-Hao Zhang, Ting-Yu Wu, and Cheng Ju conceived the idea of manuscript, Zhi-Hao Zhang and Ting-Yu Wu designed the study. Xiao-Shuang Zuo, Xuan-Kang Wang, Yang-Guang Ma, and Liang Luo performed the in vitro experiments. Zhi-Jie Zhu, Zhi-Wen Song, and Zhou Yao performed the in vivo experiment. Jie Zhou, Zhi-Hao Zhang, and Ting-Yu Wu wrote the manuscript. Zhe Wang and Xue-Yu Hu revised the manuscript and provided guidance for the project.

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Correspondence to Zhe Wang or Xue-Yu Hu.

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The design and conduct of this study were approved by the Ethics Committee of the Institutional Ethical Committee of Air Force Military Medical University guidelines (Xi'an, China) (IACUC, 20210452, date: 03–01-2021). Animal experiments for this study were performed in accordance with the Guide for the Care and Use of Laboratory Animals (National Research Council, 1996) established by the National Institutes of Health.

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Zhi-Hao Zhang, Ting-Yu Wu, and Cheng Ju contributed equally to this work and should be considered co-first authors.

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Zhang, ZH., Wu, TY., Ju, C. et al. Photobiomodulation Increases M2-Type Polarization of Macrophages by Inhibiting Versican Production After Spinal Cord Injury. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-03980-5

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