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BMP7 Attenuates Neuroinflammation after Spinal Cord Injury by Suppressing the Microglia Activation and Inducing Microglial Polarization Via the STAT3 Pathway

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Abstract

Excessive activation of pro-inflammatory (M1) microglia phenotypes after spinal cord injury (SCI) disrupts tissue repair and increases the risk of secondary SCI. We previously reported that adeno-associated virus (AAV) mediated delivery of bone morphogenetic protein 7 (BMP7) promotes functional recovery after SCI by reducing oligodendrocyte loss and demyelination; however, little is known about the early effects of BMP7 in ameliorating neuroinflammation in the acute SCI phase. Herein, we demonstrate that treatment with recombinant human BMP7 (rhBMP7) suppresses the viability of LPS-induced HMC3 microglia cells and increases the proportion with the M2 phenotype. Consistently, in a rat SCI model, rhBMP7 decreases the activation of microglia and promotes M2 polarization. After rhBMP7 administration, the STAT3 signaling pathway was activated in LPS-induced HMC3 cells and microglia in spinal cord lesions. Furthermore, the levels of TNF-α and IL-1β were significantly decreased in cell culture supernatants, lesion sites of injured spinal cords, and cerebrospinal fluid circulation after rhBMP7 administration, thus reducing neuron loss in the injured spinal cord and promoting functional recovery after SCI. These results provide insight into the immediate early mechanisms by which BMP7 may ameliorate the inflammation response to secondary SCI.

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Data Availability

The data and materials that support the findings of this study are available from the corresponding author, Yaping Wang, upon reasonable request.

References

  1. Anjum A et al (2020) Spinal cord injury: pathophysiology, multimolecular interactions, and underlying recovery mechanisms. Int J Mol Sci. https://doi.org/10.3390/ijms21207533

    Article  PubMed  PubMed Central  Google Scholar 

  2. Brockie S, Hong J, Fehlings MG (2021) The role of microglia in modulating neuroinflammation after spinal cord injury. Int J Mol Sci. https://doi.org/10.3390/ijms22189706

    Article  PubMed  PubMed Central  Google Scholar 

  3. Hassanzadeh S et al (2021) More attention on glial cells to have better recovery after spinal cord injury. Biochem Biophys Rep 25:100905. https://doi.org/10.1016/j.bbrep.2020.100905

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Wang X, Xu JM, Wang YP, Yang L, Li ZJ (2016) Protective effects of BMP-7 against tumor necrosis factor alpha-induced oligodendrocyte apoptosis. Int J Dev Neurosci 53:10–17. https://doi.org/10.1016/j.ijdevneu.2016.04.011

    Article  CAS  PubMed  Google Scholar 

  5. Liu S et al (2021) Overexpression of bone morphogenetic protein 7 reduces oligodendrocytes loss and promotes functional recovery after spinal cord injury. J Cell Mol Med 25:8764–8774. https://doi.org/10.1111/jcmm.16832

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kwon HS, Koh SH (2020) Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes. Transl Neurodegener 9:42. https://doi.org/10.1186/s40035-020-00221-2

    Article  PubMed  PubMed Central  Google Scholar 

  7. Varghese F, Bukhari AB, Malhotra R, De A (2014) IHC Profiler: an open source plugin for the quantitative evaluation and automated scoring of immunohistochemistry images of human tissue samples. PLoS ONE 9:e96801. https://doi.org/10.1371/journal.pone.0096801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Nguyen NM et al (2022) Efonidipine Inhibits JNK and NF-kappaB Pathway to Attenuate Inflammation and Cell Migration Induced by Lipopolysaccharide in Microglial Cells. Biomol Ther (Seoul) 30:455–464. https://doi.org/10.4062/biomolther.2022.076

    Article  CAS  PubMed  Google Scholar 

  9. Aguzzi A, Barres BA, Bennett ML (2013) Microglia: scapegoat, saboteur, or something else? Science 339:156–161. https://doi.org/10.1126/science.1227901

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Gerber YN et al (2018) CSF1R Inhibition Reduces Microglia Proliferation, Promotes Tissue Preservation and Improves Motor Recovery After Spinal Cord Injury. Front Cell Neurosci 12:368. https://doi.org/10.3389/fncel.2018.00368

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Wang W et al (2017) Methane Suppresses Microglial Activation Related to Oxidative, Inflammatory, and Apoptotic Injury during Spinal Cord Injury in Rats. Oxid Med Cell Longev 2017:2190897. https://doi.org/10.1155/2017/2190897

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lv R et al (2019) Polydatin alleviates traumatic spinal cord injury by reducing microglial inflammation via regulation of iNOS and NLRP3 inflammasome pathway. Int Immunopharmacol 70:28–36. https://doi.org/10.1016/j.intimp.2019.02.006

    Article  CAS  PubMed  Google Scholar 

  13. Tsai M-J et al (2007) Dual effect of adenovirus-mediated transfer of BMP7 in mixed neuron-glial cultures: Neuroprotection and cellular differentiation. J Neurosci Res 85:2950–2959. https://doi.org/10.1002/jnr.21395

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Brennan FH et al (2022) Microglia coordinate cellular interactions during spinal cord repair in mice. Nat Commun 13:4096. https://doi.org/10.1038/s41467-022-31797-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Fu H et al (2020) Depletion of microglia exacerbates injury and impairs function recovery after spinal cord injury in mice. Cell Death Dis 11:528. https://doi.org/10.1038/s41419-020-2733-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wang C et al (2018) Salidroside attenuates neuroinflammation and improves functional recovery after spinal cord injury through microglia polarization regulation. J Cell Mol Med 22:1148–1166. https://doi.org/10.1111/jcmm.13368

    Article  CAS  PubMed  Google Scholar 

  18. Akhmetzyanova E, Kletenkov K, Mukhamedshina Y, Rizvanov A (2019) Different Approaches to Modulation of Microglia Phenotypes After Spinal Cord Injury. Front Syst Neurosci 13:37. https://doi.org/10.3389/fnsys.2019.00037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Jiang CT, Wu WF, Deng YH, Ge JW (2020) Modulators of microglia activation and polarization in ischemic stroke (Review). Mol Med Rep 21:2006–2018. https://doi.org/10.3892/mmr.2020.11003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Li YF, Ren X, Zhang L, Wang YH, Chen T (2022) Microglial polarization in TBI: Signaling pathways and influencing pharmaceuticals. Front Aging Neurosci 14:901117. https://doi.org/10.3389/fnagi.2022.901117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Castro LVG, Goncalves-de-Albuquerque CF, Silva AR (2022) Polarization of Microglia and Its Therapeutic Potential in Sepsis. Int J Mol Sci. https://doi.org/10.3390/ijms23094925

    Article  PubMed  PubMed Central  Google Scholar 

  22. Dziennis S, Alkayed NJ (2008) Role of signal transducer and activator of transcription 3 in neuronal survival and regeneration. Rev Neurosci 19:341–361. https://doi.org/10.1515/revneuro.2008.19.4-5.341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Zhong Y et al (2022) JAK2/STAT3 Axis Intermediates Microglia/Macrophage Polarization During Cerebral Ischemia/Reperfusion Injury. Neuroscience 496:119–128. https://doi.org/10.1016/j.neuroscience.2022.05.016

    Article  CAS  PubMed  Google Scholar 

  24. Liu ZJ et al (2019) Melatonin protects against ischemic stroke by modulating microglia/macrophage polarization toward anti-inflammatory phenotype through STAT3 pathway. CNS Neurosci Ther 25:1353–1362. https://doi.org/10.1111/cns.13261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Yang L, Liu S, Wang Y (2019) Role of bone morphogenetic protein-2/4 in astrocyte activation in neuropathic pain. Mol Pain 15:1744806919892100. https://doi.org/10.1177/1744806919892100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Rajan P, Panchision DM, Newell LF, McKay RDG (2003) BMPs signal alternately through a SMAD or FRAP–STAT pathway to regulate fate choice in CNS stem cells. J Cell Biol 161:911–921. https://doi.org/10.1083/jcb.200211021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Yu D et al (2022) Inhibition of STAT3 signaling pathway by terphenyllin suppresses growth and metastasis of gastric cancer. Front Pharmacol 13:870367. https://doi.org/10.3389/fphar.2022.870367

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Jo S et al (2021) STAT3 phosphorylation inhibition for treating inflammation and new bone formation in ankylosing spondylitis. Rheumatology (Oxford) 60:3923–3935. https://doi.org/10.1093/rheumatology/keaa846

    Article  CAS  PubMed  Google Scholar 

  29. Le Dreau G et al (2012) Canonical BMP7 activity is required for the generation of discrete neuronal populations in the dorsal spinal cord. Development 139:259–268. https://doi.org/10.1242/dev.074948

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ortega JA, Alcantara S (2010) BDNF/MAPK/ERK-induced BMP7 expression in the developing cerebral cortex induces premature radial glia differentiation and impairs neuronal migration. Cereb Cortex 20:2132–2144. https://doi.org/10.1093/cercor/bhp275

    Article  PubMed  Google Scholar 

  31. Bragdon B et al (2011) Bone morphogenetic proteins: a critical review. Cell Signal 23:609–620. https://doi.org/10.1016/j.cellsig.2010.10.003

    Article  CAS  PubMed  Google Scholar 

  32. Pei H et al (2013) Bone morphogenetic protein-7 ameliorates cerebral ischemia and reperfusion injury via inhibiting oxidative stress and neuronal apoptosis. Int J Mol Sci 14:23441–23453. https://doi.org/10.3390/ijms141223441

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Tsai MJ et al (2010) Adenoviral gene transfer of bone morphogenetic protein-7 enhances functional recovery after sciatic nerve injury in rats. Gene Ther 17:1214–1224. https://doi.org/10.1038/gt.2010.72

    Article  CAS  PubMed  Google Scholar 

  34. Elmadbouh I, Singla DK (2021) BMP-7 attenuates inflammation-induced pyroptosis and improves cardiac repair in diabetic cardiomyopathy. Cells. https://doi.org/10.3390/cells10102640

    Article  PubMed  PubMed Central  Google Scholar 

  35. Aluganti Narasimhulu C, Singla DK (2020) the role of bone morphogenetic protein 7 (BMP-7) in inflammation in heart diseases. Cells. https://doi.org/10.3390/cells9020280

    Article  PubMed  PubMed Central  Google Scholar 

  36. Stumm CL et al (2014) Lung remodeling in a mouse model of asthma involves a balance between TGF-beta1 and BMP-7. PLoS ONE 9:e95959. https://doi.org/10.1371/journal.pone.0095959

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Chen C, Bai GC, Jin HL, Lei K, Li KX (2018) Local injection of bone morphogenetic protein 7 promotes neuronal regeneration and motor function recovery after acute spinal cord injury. Neural Regen Res 13:1054–1060. https://doi.org/10.4103/1673-5374.233449

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank LetPub (www.letpub.com) for linguistic assistance and pre-submission expert review and the support from the Natural Science Foundation of Hunan Province (Grant Numbers: 2020JJ4811).

Funding

The Natural Science Foundation of Hunan Province, 2020JJ4811, The Key Research and Development Program of Hunan Province, 2020SK2097.

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Author notes

  1. Xiaojin Wei and Chaodong Huang have contributed equally to this work.

Authors and Affiliations

  1. Department of Pain Management and Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China

    Xiaojin Wei, Chaodong Huang, Kai Chen, Meng Wang, Lin Yang & Yaping Wang

  2. Department of Pain Management and Anesthesiology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China

    Shuxin Liu

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WY and WX conceived the idea; WX and HC conducted the analyses and interpreted the results; all authors contributed to the writing and revisions.

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Correspondence to Yaping Wang.

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Wei, X., Huang, C., Chen, K. et al. BMP7 Attenuates Neuroinflammation after Spinal Cord Injury by Suppressing the Microglia Activation and Inducing Microglial Polarization Via the STAT3 Pathway. Neurochem Res 48, 2687–2700 (2023). https://doi.org/10.1007/s11064-023-03930-y

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