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Multinucleated Giant Cells in Experimental Intracerebral Hemorrhage

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Abstract

Macrophage phagocytosis plays an important role in hematoma clearance after intracerebral hemorrhage (ICH). This study examined the characteristics of multinucleated giant cells (MGCs), a group of macrophages with multiple nuclei, in a mouse ICH model. Whether MGCs could be increased by treatment with a CD47 blocking antibody and decreased by treatment with clodronate liposomes were also examined. ICH was induced via autologous blood injection. Male adult C57BL/6 mice in different groups had (1) ICH alone; (2) ICH with anti-CD47 blocking antibody or control IgG; and (3) ICH with anti-CD47 antibody combined with clodronate liposomes or control liposomes. The effect of anti-CD47 antibody on MGC formation was also tested in females. Brains were harvested at days 3 or 7 for brain histology. Many MGCs were found at day 3 post-ICH, but were reduced at day 7. MGCs phagocytosed many red blood cells and were heme oxygenase-1, ferritin, YM-1, and iNOS positive. CD47 blocking antibody injection increased MGC numbers in the peri-hematomal zone and in the hematoma in both sexes. Co-injection of clodronate liposomes depleted MGCs in both the hematoma core and the peri-hematomal area. In conclusion, MGCs represent a macrophage/microglia subtype with strong phagocytosis capacity. MGCs exhibited not only an M2 but also an M1 phenotype and appeared involved in hemoglobin degradation. Anti-CD47 antibody boosted the number of MGCs, which may contribute to enhance hematoma clearance. Understanding the exact roles of MGCs in ICH may reveal novel targets for ICH treatment.

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References

  1. Hankey GJ. Stroke. Lancet. 2017;389:641–54.

    Article  Google Scholar 

  2. Xi G, Keep RF, Hoff JT. Mechanisms of brain injury after intracerebral hemorrhage. Lancet Neurol. 2006;5:53–63.

    Article  Google Scholar 

  3. Keep RF, Andjelkovic AV, Xiang J, Stamatovic SM, Antonetti DA, Hua Y, et al. Brain endothelial cell junctions after cerebral hemorrhage: changes, mechanisms and therapeutic targets. J Cereb Blood Flow Metab. 2018;38:1255–75.

    Article  CAS  Google Scholar 

  4. Keep RF, Hua Y, Xi G. Intracerebral haemorrhage: mechanisms of injury and therapeutic targets. Lancet Neurol. 2012;11:720–31.

    Article  CAS  Google Scholar 

  5. Wilkinson DA, Keep RF, Hua Y, Xi G. Hematoma clearance as a therapeutic target in intracerebral hemorrhage: from macro to micro. J Cereb Blood Flow Metab. 2018;38:741–5.

    Article  Google Scholar 

  6. Liu R, Li H, Hua Y, Keep RF, Xiao J, Xi G, et al. Early hemolysis within human intracerebral hematomas: an mri study. Transl Stroke Res. 2019;10:52–6.

    Article  CAS  Google Scholar 

  7. Hanley DF, Thompson RE, Rosenblum M, Yenokyan G, Lane K, McBee N, et al. Efficacy and safety of minimally invasive surgery with thrombolysis in intracerebral haemorrhage evacuation (mistie iii): a randomised, controlled, open-label, blinded endpoint phase 3 trial. Lancet. 2019;393:1021–32.

    Article  Google Scholar 

  8. Chang CF, Goods BA, Askenase MH, Hammond MD, Renfroe SC, Steinschneider AF, et al. Erythrocyte efferocytosis modulates macrophages towards recovery after intracerebral hemorrhage. J Clin Invest. 2018;128:607–24.

    Article  Google Scholar 

  9. Jing C, Bian L, Wang M, Keep RF, Xi G, Hua Y. Enhancement of hematoma clearance with cd47 blocking antibody in experimental intracerebral hemorrhage. Stroke. 2019;50:1539–47.

    Article  CAS  Google Scholar 

  10. Quinn MT, Schepetkin IA. Role of nadph oxidase in formation and function of multinucleated giant cells. J Innate Immun. 2009;1:509–26.

    Article  CAS  Google Scholar 

  11. Chambers TJ, Spector WG. Inflammatory giant cells. Immunobiology. 1982;161:283–9.

    Article  CAS  Google Scholar 

  12. Shtaya A, Bridges LR, Esiri MM, Lam-Wong J, Nicoll JAR, Boche D, et al. Rapid neuroinflammatory changes in human acute intracerebral hemorrhage. Ann Clin Transl Neurol. 2019;6:1465–79.

    PubMed  PubMed Central  CAS  Google Scholar 

  13. Yenari MA, Kauppinen TM, Swanson RA. Microglial activation in stroke: therapeutic targets. Neurotherapeutics. 2010;7:378–91.

    Article  CAS  Google Scholar 

  14. Block ML, Zecca L, Hong JS. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci. 2007;8:57–69.

    Article  CAS  Google Scholar 

  15. Nakajima K, Yamamoto S, Kohsaka S, Kurihara T. Neuronal stimulation leading to upregulation of glutamate transporter-1 (glt-1) in rat microglia in vitro. Neurosci Lett. 2008;436:331–4.

    Article  CAS  Google Scholar 

  16. Thored P, Heldmann U, Gomes-Leal W, Gisler R, Darsalia V, Taneera J, et al. Long-term accumulation of microglia with proneurogenic phenotype concomitant with persistent neurogenesis in adult subventricular zone after stroke. Glia. 2009;57:835–49.

    Article  Google Scholar 

  17. Ni W, Mao S, Xi G, Keep RF, Hua Y. Role of erythrocyte cd47 in intracerebral hematoma clearance. Stroke. 2016;47:505–11.

    Article  CAS  Google Scholar 

  18. Liu H, Hua Y, Keep RF, Xi G. Brain ceruloplasmin expression after experimental intracerebral hemorrhage and protection against iron-induced brain injury. Transl Stroke Res. 2019;10:112–9.

    Article  CAS  Google Scholar 

  19. Ghorpade A, Persidsky Y, Swindells S, Borgmann K, Persidsky R, Holter S, et al. Neuroinflammatory responses from microglia recovered from hiv-1-infected and seronegative subjects. J Neuroimmunol. 2005;163:145–56.

    Article  CAS  Google Scholar 

  20. Fendrick SE, Xue QS, Streit WJ. Formation of multinucleated giant cells and microglial degeneration in rats expressing a mutant cu/zn superoxide dismutase gene. J Neuroinflammation. 2007;4:9.

    Article  CAS  Google Scholar 

  21. Vignery A. Macrophage fusion: molecular mechanisms. Methods Mol Biol. 2008;475:149–61.

    Article  Google Scholar 

  22. Ruibal-Ares B, Riera NE, de Bracco MM. Macrophages, multinucleated giant cells, and apoptosis in hiv+ patients and normal blood donors. Clin Immunol Immunopathol. 1997;82:102–16.

    Article  CAS  Google Scholar 

  23. McNally AK, Anderson JM. Macrophage fusion and multinucleated giant cells of inflammation. Adv Exp Med Biol. 2011;713:97–111.

    Article  CAS  Google Scholar 

  24. McNally AK, Anderson JM. Multinucleated giant cell formation exhibits features of phagocytosis with participation of the endoplasmic reticulum. Exp Mol Pathol. 2005;79:126–35.

    Article  CAS  Google Scholar 

  25. Normand G, King RW. Understanding cytokinesis failure. Adv Exp Med Biol. 2010;676:27–55.

    Article  CAS  Google Scholar 

  26. Bachstetter AD, Van Eldik LJ, Schmitt FA, Neltner JH, Ighodaro ET, Webster SJ, et al. Disease-related microglia heterogeneity in the hippocampus of alzheimer’s disease, dementia with lewy bodies, and hippocampal sclerosis of aging. Acta Neuropathol Commun. 2015;3:32.

    Article  CAS  Google Scholar 

  27. Yamada J, Jinno S. Novel objective classification of reactive microglia following hypoglossal axotomy using hierarchical cluster analysis. J Comp Neurol. 2013;521:1184–201.

    Article  CAS  Google Scholar 

  28. Zhao H, Garton T, Keep RF, Hua Y, Xi G. Microglia/macrophage polarization after experimental intracerebral hemorrhage. Transl Stroke Res. 2015;6:407–9.

    Article  Google Scholar 

  29. Burger P, Hilarius-Stokman P, de Korte D, van den Berg TK, van Bruggen R. Cd47 functions as a molecular switch for erythrocyte phagocytosis. Blood. 2012;119:5512–21.

    Article  CAS  Google Scholar 

  30. Han X, Sterling H, Chen Y, Saginario C, Brown EJ, Frazier WA, et al. Cd47, a ligand for the macrophage fusion receptor, participates in macrophage multinucleation. J Biol Chem. 2000;275:37984–92.

    Article  CAS  Google Scholar 

  31. Griesmann H, Drexel C, Milosevic N, Sipos B, Rosendahl J, Gress TM, et al. Pharmacological macrophage inhibition decreases metastasis formation in a genetic model of pancreatic cancer. Gut. 2017;66:1278–85.

    Article  CAS  Google Scholar 

  32. Danenberg HD, Fishbein I, Gao J, Monkkonen J, Reich R, Gati I, et al. Macrophage depletion by clodronate-containing liposomes reduces neointimal formation after balloon injury in rats and rabbits. Circulation. 2002;106:599–605.

    Article  CAS  Google Scholar 

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Funding

YH, RFK, and GX are supported by grants NS-091545, NS-090925, NS-096917, NS-106746, and NS-112394 from the National Institutes of Health (NIH).

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Correspondence to Guohua Xi.

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Jialiang Wei, Ming Wang, Chaohui Jing, Richard F. Keep, Ya Hua, and Guohua Xi declare that they have no conflict of interest.

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All institutional and national guidelines for the care and use of laboratory animals were followed.

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Wei, J., Wang, M., Jing, C. et al. Multinucleated Giant Cells in Experimental Intracerebral Hemorrhage. Transl. Stroke Res. 11, 1095–1102 (2020). https://doi.org/10.1007/s12975-020-00790-4

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