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S100B promotes microglia M1 polarization and migration to aggravate cerebral ischemia

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Abstract

Aim and objective

S100B has been found abundantly expressed in microglia during cerebral ischemia. However, S100B effects on phenotype changes and migration of microglia are unclear.

Methods

Real-time PCR of S100B, M1 and M2 markers were tested to characterize phenotypic changes in microglia in mice middle cerebral artery occlusion (MCAO) model. Migration assay and additional mechanism studies were performed to elucidate the role of NF-κB in S100B-mediated microglia M1/M2 phenotype change and migration. Finally, S100B treatment on MCAO models was performed to show the in vivo evidence.

Results

S100B was identified as an induced gene with its pattern in accordance with M1 markers in mice MCAO model. That S100B was promoted by M1 stimuli whereas inhibited by M2 stimuli further confirmed S100B a M1 marker. Moreover, S100B promotes microglia M1 polarization with enhanced migration ability and inhibits M2 polarization. Additionally, NF-κB is essential in S100B control in microglia M1/M2 polarization and migration. Furthermore, S100B aggravated cerebral ischemia in murine MCAO model and exacerbated the microglia M1 polarization and migration.

Conclusions

Our findings demonstrate that S100B promotes microglia M1 polarization to aggravate cerebral ischemia, and provide a better understanding on the therapeutic effects of S100B and/or its antagonist/neutralization antibody in stroke.

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References

  1. Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, et al. Heart disease and stroke statistics-2017 update: a report from the American Heart Association. Circulation. 2017;135:e146–603.

    Article  Google Scholar 

  2. Zhang B, Wu T, Song C, Chen M, Li H, Guo R. Association of CD40–1C/T polymorphism with cerebral infarction susceptibility and its effect on sCD40L in Chinese population. Int Immunopharmacol. 2013;16:461–5.

    Article  CAS  Google Scholar 

  3. Arboix A, Alio J. Cardioembolic stroke: clinical features, specific cardiac disorders and prognosis. Curr Cardiol Rev. 2010;6:150–61.

    Article  Google Scholar 

  4. Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischaemic stroke: an integrated view. Trends in neurosciences. 1999;22:391–7.

    Article  CAS  Google Scholar 

  5. Hossmann KA. Pathophysiology and therapy of experimental stroke. Cell Mol Neurobiol. 2006;26:1057–83.

    Article  Google Scholar 

  6. Trendelenburg G, Dirnagl U. Neuroprotective role of astrocytes in cerebral ischemia: focus on ischemic preconditioning. Glia. 2005;50:307–20.

    Article  Google Scholar 

  7. Amor S, Puentes F, Baker D, van der Valk P. Inflammation in neurodegenerative diseases. Immunology. 2010;129:154–69.

    Article  CAS  Google Scholar 

  8. ** X, Ishii H, Bai Z, Itokazu T, Yamashita T. Temporal changes in cell marker expression and cellular infiltration in a controlled cortical impact model in adult male C57BL/6 mice. PLoS One. 2012;7:e41892.

    Article  CAS  Google Scholar 

  9. ** R, Yang G, Li G. Inflammatory mechanisms in ischemic stroke: role of inflammatory cells. J Leukoc Biol. 2010;87:779–89.

    Article  CAS  Google Scholar 

  10. Kigerl KA, Gensel JC, Ankeny DP, Alexander JK, Donnelly DJ, Popovich PG. Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J Neurosci. 2009;29:13435–44.

    Article  CAS  Google Scholar 

  11. Perry VH, Nicoll JA, Holmes C. Microglia in neurodegenerative disease. Nat Rev Neurol. 2010;6:193–201.

    Article  Google Scholar 

  12. Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008;8:958–69.

    Article  CAS  Google Scholar 

  13. Goerdt S, Politz O, Schledzewski K, Birk R, Gratchev A, Guillot P, et al. Alternative versus classical activation of macrophages. Pathobiol J Immunopathol Mol Cell Biol. 1999;67:222–6.

    Article  CAS  Google Scholar 

  14. Durafourt BA, Moore CS, Zammit DA, Johnson TA, Zaguia F, Guiot MC, et al. Comparison of polarization properties of human adult microglia and blood-derived macrophages. Glia. 2012;60:717–27.

    Article  Google Scholar 

  15. Hu X, Li P, Guo Y, Wang H, Leak RK, Chen S, et al. Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia. Stroke. 2012;43:3063–70.

    Article  CAS  Google Scholar 

  16. Wang G, Zhang J, Hu X, Zhang L, Mao L, Jiang X, et al. Microglia/macrophage polarization dynamics in white matter after traumatic brain injury. J Cereb Blood Flow Metab. 2013;33:1864–74.

    Article  CAS  Google Scholar 

  17. Frieler RA, Meng H, Duan SZ, Berger S, Schutz G, He Y, et al. Myeloid-specific deletion of the mineralocorticoid receptor reduces infarct volume and alters inflammation during cerebral ischemia. Stroke. 2011;42:179–85.

    Article  Google Scholar 

  18. Nedergaard M, Dirnagl U. Role of glial cells in cerebral ischemia. Glia. 2005;50:281–6.

    Article  Google Scholar 

  19. Donato R, Cannon BR, Sorci G, Riuzzi F, Hsu K, Weber DJ, et al. Functions of S100 proteins. Curr Mol Med. 2013;13:24–57.

    Article  CAS  Google Scholar 

  20. Sun BD, Liu HM, Nie SN. S100B protein in serum is elevated after global cerebral ischemic injury. World J Emerg Med. 2013;4:165–8.

    Article  Google Scholar 

  21. Foerch C, Singer OC, Neumann-Haefelin T, du Mesnil de Rochemont R, Steinmetz H, Sitzer M. Evaluation of serum S100B as a surrogate marker for long-term outcome and infarct volume in acute middle cerebral artery infarction. Arch Neurol. 2005;62:1130–4.

    Article  Google Scholar 

  22. Hu J, Castets F, Guevara JL, Van Eldik LJ. S100 beta stimulates inducible nitric oxide synthase activity and mRNA levels in rat cortical astrocytes. J Biol Chem. 1996;271:2543–7.

    Article  CAS  Google Scholar 

  23. Lam AG, Koppal T, Akama KT, Guo L, Craft JM, Samy B, et al. Mechanism of glial activation by S100B: involvement of the transcription factor NFkappaB. Neurobiol Aging. 2001;22:765–72.

    Article  CAS  Google Scholar 

  24. Bianchi R, Kastrisianaki E, Giambanco I, Donato R. S100B protein stimulates microglia migration via RAGE-dependent up-regulation of chemokine expression and release. J Biol Chem. 2011;286:7214–26.

    Article  CAS  Google Scholar 

  25. Liu F, Schafer DP, McCullough LD. TTC, fluoro-Jade B and NeuN staining confirm evolving phases of infarction induced by middle cerebral artery occlusion. J Neurosci Methods. 2009;179:1–8.

    Article  CAS  Google Scholar 

  26. Orihuela R, McPherson CA, Harry GJ. Microglial M1/M2 polarization and metabolic states. Br J Pharmacol. 2016;173:649–65.

    Article  CAS  Google Scholar 

  27. Schuette-Nuetgen K, Strecker JK, Minnerup J, Ringelstein EB, Schilling M. MCP-1/CCR-2-double-deficiency severely impairs the migration of hematogenous inflammatory cells following transient cerebral ischemia in mice. Exp Neurol. 2012;233:849–58.

    Article  CAS  Google Scholar 

  28. Starossom SC, Mascanfroni ID, Imitola J, Cao L, Raddassi K, Hernandez SF, et al. Galectin-1 deactivates classically activated microglia and protects from inflammation-induced neurodegeneration. Immunity. 2012;37:249–63.

    Article  CAS  Google Scholar 

  29. Donato R, Sorci G, Riuzzi F, Arcuri C, Bianchi R, Brozzi F, et al. S100B’s double life: intracellular regulator and extracellular signal. Biochimica et biophysica acta. 2009;1793:1008–22.

    Article  CAS  Google Scholar 

  30. Loane DJ, Byrnes KR. Role of microglia in neurotrauma. Neurotherapeutics. 2010;7:366–77.

    Article  CAS  Google Scholar 

  31. Lalancette-Hebert M, Gowing G, Simard A, Weng YC, Kriz J. Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain. J Neurosci. 2007;27:2596–605.

    Article  CAS  Google Scholar 

  32. Hanisch UK, Kettenmann H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci. 2007;10:1387–94.

    Article  CAS  Google Scholar 

  33. Lull ME, Block ML. Microglial activation and chronic neurodegeneration. Neurotherapeutics. 2010;7:354–65.

    Article  CAS  Google Scholar 

  34. Shao Y, Deng T, Zhang T, Li P, Wang Y. FAM19A3, a novel secreted protein, modulates the microglia/macrophage polarization dynamics and ameliorates cerebral ischemia. FEBS Lett. 2015;589:467–75.

    Article  CAS  Google Scholar 

  35. Kobayashi K, Imagama S, Ohgomori T, Hirano K, Uchimura K, Sakamoto K, et al. Minocycline selectively inhibits M1 polarization of microglia. Cell Death Dis. 2013;4:e525.

    Article  CAS  Google Scholar 

  36. Paintlia AS, Paintlia MK, Singh I, Singh AK. IL-4-induced peroxisome proliferator-activated receptor gamma activation inhibits NF-kappaB trans activation in central nervous system (CNS) glial cells and protects oligodendrocyte progenitors under neuroinflammatory disease conditions: implication for CNS-demyelinating diseases. J Immunol. 2006;176:4385–98.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by Grant from Wenzhou Science and Technology Bureau Public Welfare Social Development (Medical and Health) Science and Technology Project Foundation (Y20150026).

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Correspondence to Jianhong Bao.

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Responsible Editor: John Di Battista.

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Zhou, S., Zhu, W., Zhang, Y. et al. S100B promotes microglia M1 polarization and migration to aggravate cerebral ischemia. Inflamm. Res. 67, 937–949 (2018). https://doi.org/10.1007/s00011-018-1187-y

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  • DOI: https://doi.org/10.1007/s00011-018-1187-y

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