Abstract
Evidence indicates that erythrocyte-derived iron and inflammation both play a role in intraventricular hemorrhage-induced brain injury including hydrocephalus. Many immune-associated cells, primarily stromal macrophages, reside at the choroid plexus where they are involved in inflammatory responses and antigen presentation. However, whether intraventricular iron impacts those stromal cells is unknown. The aim of this study was to evaluate the relationship between choroid plexus stromal macrophages and iron-induced hydrocephalus in rats and the impact of minocycline and clodronate liposomes on those changes. Aged (18-month-old) and young (3-month-old) male Fischer 344 rats were used to study choroid plexus stromal macrophages. Rats underwent intraventricular iron injection to induce hydrocephalus and treated with either minocycline, a microglia/macrophage inhibitor, or clodronate liposomes, a macrophage depleting agent. Ventricular volume was measured using magnetic resonance imaging, and stromal macrophages were quantified by immunofluorescence staining. We found that stromal macrophages accounted for about 10% of the total choroid plexus cells with more in aged rats. In both aged and young rats, intraventricular iron injection resulted in hydrocephalus and increased stromal macrophage number. Minocycline or clodronate liposomes ameliorated iron-induced hydrocephalus and the increase in stromal macrophages. In conclusion, stromal macrophages account for ~10% of all choroid plexus cells, with more in aged rats. Treatments targeting macrophages (minocycline and clodronate liposomes) are associated with reduced iron-induced hydrocephalus.
Similar content being viewed by others
Data Availability
Data will be available on reasonable request.
References
Lun MP, Monuki ES, Lehtinen MK. Development and functions of the choroid plexus-cerebrospinal fluid system. Nat Rev Neurosci. 2015;16(8):445–57. https://doi.org/10.1038/nrn3921.
Kaur C, Rathnasamy G, Ling EA. The choroid plexus in healthy and diseased brain. J Neuropathol Exp Neurol. 2016;75(3):198–213. https://doi.org/10.1093/jnen/nlv030.
Marques F, Sousa JC, Brito MA, Pahnke J, Santos C, Correia-Neves M, et al. The choroid plexus in health and in disease: dialogues into and out of the brain. Neurobiol Dis. 2017;107:32–40. https://doi.org/10.1016/j.nbd.2016.08.011.
Castro Dias M, Mapunda JA, Vladymyrov M, Engelhardt B. Structure and junctional complexes of endothelial, epithelial and glial brain barriers. Int J Mol Sci. 2019;20(21). https://doi.org/10.3390/ijms20215372.
Ghersi-Egea JF, Strazielle N, Catala M, Silva-Vargas V, Doetsch F, Engelhardt B. Molecular anatomy and functions of the choroidal blood-cerebrospinal fluid barrier in health and disease. Acta Neuropathol. 2018;135(3):337–61. https://doi.org/10.1007/s00401-018-1807-1.
Karimy JK, Reeves BC, Damisah E, Duy PQ, Antwi P, David W, et al. Inflammation in acquired hydrocephalus: pathogenic mechanisms and therapeutic targets. Nat Rev Neurol. 2020;16(5):285–96. https://doi.org/10.1038/s41582-020-0321-y.
McMenamin PG, Wealthall RJ, Deverall M, Cooper SJ, Griffin B. Macrophages and dendritic cells in the rat meninges and choroid plexus: three-dimensional localisation by environmental scanning electron microscopy and confocal microscopy. Cell Tissue Res. 2003;313(3):259–69. https://doi.org/10.1007/s00441-003-0779-0.
Ling EA, Kaur C, Lu J. Origin, nature, and some functional considerations of intraventricular macrophages, with special reference to the epiplexus cells. Microscopy research and technique. 1998;41(1):43–56. https://doi.org/10.1002/(SICI)1097-0029(19980401)41:1<43::AID-JEMT5>3.0.CO;2-V.
Mundt S, Mrdjen D, Utz SG, Greter M, Schreiner B, Becher B. Conventional DCs sample and present myelin antigens in the healthy CNS and allow parenchymal T cell entry to initiate neuroinflammation. Sci Immunol. 2019;4(31). https://doi.org/10.1126/sciimmunol.aau8380.
Dando SJ, Kazanis R, Chinnery HR, McMenamin PG. Regional and functional heterogeneity of antigen presenting cells in the mouse brain and meninges. Glia. 2019;67(5):935–49. https://doi.org/10.1002/glia.23581.
Rodriguez-Lorenzo S, Konings J, van der Pol S, Kamermans A, Amor S, van Horssen J, et al. Inflammation of the choroid plexus in progressive multiple sclerosis: accumulation of granulocytes and T cells. Acta Neuropathol Commun. 2020;8(1):9. https://doi.org/10.1186/s40478-020-0885-1.
Bosche B, Mergenthaler P, Doeppner TR, Hescheler J, Molcanyi M. Complex clearance mechanisms after intraventricular hemorrhage and rt-PA treatment-a review on clinical trials. Transl Stroke Res. 2020;11(3):337–44. https://doi.org/10.1007/s12975-019-00735-6.
Hanley DF. Intraventricular hemorrhage: severity factor and treatment target in spontaneous intracerebral hemorrhage. Stroke. 2009;40(4):1533-8. doi: STROKEAHA.108.535419 [pii] 10.1161/STROKEAHA.108.535419.
Hemorrhagic Stroke Academia Industry Roundtable P. Basic and translational research in intracerebral hemorrhage: limitations, priorities, and recommendations. Stroke. 2018;49(5):1308–14. https://doi.org/10.1161/STROKEAHA.117.019539.
Keep RF, Hua Y, Xi G. Intracerebral haemorrhage: mechanisms of injury and therapeutic targets. Lancet Neurol. 2012;11(8):720–31. https://doi.org/10.1016/S1474-4422(12)70104-7.
Chen Z, Gao C, Hua Y, Keep RF, Muraszko K, Xi G. Role of iron in brain injury after intraventricular hemorrhage. Stroke. 2011;42(2):465-70. doi: STROKEAHA.110.602755 [pii] 10.1161/STROKEAHA.110.602755.
Garton T, Hua Y, Xiang J, Xi G, Keep RF. Challenges for intraventricular hemorrhage research and emerging therapeutic targets. Expert Opin Ther Targets. 2017;21(12):1111–22. https://doi.org/10.1080/14728222.2017.1397628.
Gu C, Hao X, Li J, Hua Y, Keep RF, Xi G. Effects of minocycline on epiplexus macrophage activation, choroid plexus injury and hydrocephalus development in spontaneous hypertensive rats. J Cereb Blood Flow Metab. 2019;39(10):1936–48. https://doi.org/10.1177/0271678X19836117.
Okubo S, Strahle J, Keep RF, Hua Y, Xi G. Subarachnoid hemorrhage-induced hydrocephalus in rats. Stroke. 2013;44(2):547–50. https://doi.org/10.1161/STROKEAHA.112.662312.
Strahle JM, Garton T, Bazzi AA, Kilaru H, Garton HJ, Maher CO, et al. Role of hemoglobin and iron in hydrocephalus after neonatal intraventricular hemorrhage. Neurosurgery. 2014;75(6):696–705; discussion 6. https://doi.org/10.1227/NEU.0000000000000524.
Gao C, Du H, Hua Y, Keep RF, Strahle J, Xi G. Role of red blood cell lysis and iron in hydrocephalus after intraventricular hemorrhage. J Cereb Blood Flow Metab. 2014;34(6):1070–5. https://doi.org/10.1038/jcbfm.2014.56.
Meng H, Li F, Hu R, Yuan Y, Gong G, Hu S, et al. Deferoxamine alleviates chronic hydrocephalus after intraventricular hemorrhage through iron chelation and Wnt1/Wnt3a inhibition. Brain Res. 2015;1602:44–52. https://doi.org/10.1016/j.brainres.2014.08.039.
Xu H, Tan G, Zhang S, Zhu H, Liu F, Huang C, et al. Minocycline reduces reactive gliosis in the rat model of hydrocephalus. BMC Neurosci. 2012;13:148. https://doi.org/10.1186/1471-2202-13-148.
Machado LS, Sazonova IY, Kozak A, Wiley DC, El-Remessy AB, Ergul A, et al. Minocycline and tissue-type plasminogen activator for stroke: assessment of interaction potential. Stroke. 2009;40(9):3028-33. doi: STROKEAHA.109.556852 [pii] 10.1161/STROKEAHA.109.556852.
Cao S, Hua Y, Keep RF, Chaudhary N, Xi G. Minocycline effects on intracerebral hemorrhage-induced iron overload in aged rats: brain iron quantification with magnetic resonance imaging. stroke. 2018;49(4):995–1002. https://doi.org/10.1161/STROKEAHA.117.019860.
McAllister JP 2nd, Miller JM. Minocycline inhibits glial proliferation in the H-Tx rat model of congenital hydrocephalus. Cerebrospinal Fluid Res. 2010;7:7. https://doi.org/10.1186/1743-8454-7-7.
Yang Y, Zhang K, Yin X, Lei X, Chen X, Wang J, et al. Quantitative iron neuroimaging can be used to assess the effects of minocycline in an intracerebral hemorrhage minipig model. Transl Stroke Res. 2020;11(3):503–16. https://doi.org/10.1007/s12975-019-00739-2.
van Rooijen N, Sanders A. Elimination, blocking, and activation of macrophages: three of a kind? J Leukoc Biol. 1997;62(6):702–9. https://doi.org/10.1002/jlb.62.6.702.
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(6):1539–47. https://doi.org/10.1161/STROKEAHA.118.024578.
Wei J, Wang M, Jing C, Keep RF, Hua Y, Xi G. Multinucleated giant cells in experimental intracerebral hemorrhage. Transl Stroke Res. 2020;11(5):1095–102. https://doi.org/10.1007/s12975-020-00790-4.
Polfliet MM, Goede PH, van Kesteren-Hendrikx EM, van Rooijen N, Dijkstra CD, van den Berg TK. A method for the selective depletion of perivascular and meningeal macrophages in the central nervous system. J Neuroimmunol. 2001;116(2):188–95.
Zhang J, Novakovic N, Hua Y, Keep RF, Xi G. Role of lipocalin-2 in extracellular peroxiredoxin 2-induced brain swelling, inflammation and neuronal death. Exp Neurol. 2021;335:113521. https://doi.org/10.1016/j.expneurol.2020.113521.
Ransohoff RM, Engelhardt B. The anatomical and cellular basis of immune surveillance in the central nervous system. Nat Rev Immunol. 2012;12(9):623–35. https://doi.org/10.1038/nri3265.
Wan Y, Gao F, Ye F, Yang W, Hua Y, Keep RF, et al. Effects of aging on hydrocephalus after intraventricular hemorrhage. Fluids Barriers CNS. 2020;17(1):8. https://doi.org/10.1186/s12987-020-0169-y.
Rivest S. Molecular insights on the cerebral innate immune system. Brain Behav Immun. 2003;17(1):13–9. https://doi.org/10.1016/s0889-1591(02)00055-7.
Karimy JK, Zhang J, Kurland DB, Theriault BC, Duran D, Stokum JA, et al. Inflammation-dependent cerebrospinal fluid hypersecretion by the choroid plexus epithelium in posthemorrhagic hydrocephalus. Nat Med. 2017;23(8):997–1003. https://doi.org/10.1038/nm.4361.
Yenari MA, Xu L, Tang XN, Qiao Y, Giffard RG. Microglia potentiate damage to blood-brain barrier constituents: improvement by minocycline in vivo and in vitro. Stroke. 2006;37(4):1087-93. doi: 01.STR.0000206281.77178.ac [pii] 10.1161/01.STR.0000206281.77178.ac.
Tikka TM, Koistinaho JE. Minocycline provides neuroprotection against N-methyl-D-aspartate neurotoxicity by inhibiting microglia. J Immunol. 2001;166(12):7527–33. https://doi.org/10.4049/jimmunol.166.12.7527.
Van Rooijen N, Sanders A. Liposome mediated depletion of macrophages: mechanism of action, preparation of liposomes and applications. J Immunol Methods. 1994;174(1-2):83–93. https://doi.org/10.1016/0022-1759(94)90012-4.
Wang YR, Mao XF, Wu HY, Wang YX. Liposome-encapsulated clodronate specifically depletes spinal microglia and reduces initial neuropathic pain. Biochem Biophys Res Commun. 2018;499(3):499–505. https://doi.org/10.1016/j.bbrc.2018.03.177.
Serot JM, Foliguet B, Bene MC, Faure GC. Choroid plexus and ageing in rats: a morphometric and ultrastructural study. Eur J Neurosci. 2001;14(5):794–8. https://doi.org/10.1046/j.0953-816x.2001.01693.x.
Preston JE. Ageing choroid plexus-cerebrospinal fluid system. Microsc Res Tech. 2001;52(1):31–7. https://doi.org/10.1002/1097-0029(20010101)52:1<31::AID-JEMT5>3.0.CO;2-T.
Chen RL, Kassem NA, Redzic ZB, Chen CP, Segal MB, Preston JE. Age-related changes in choroid plexus and blood-cerebrospinal fluid barrier function in the sheep. Exp Gerontol. 2009;44(4):289–96. https://doi.org/10.1016/j.exger.2008.12.004.
Honarpisheh P, Blixt FW, Blasco Conesa MP, Won W, d'Aigle J, Munshi Y, et al. Peripherally-sourced myeloid antigen presenting cells increase with advanced aging. Brain Behav Immun. 2020. https://doi.org/10.1016/j.bbi.2020.08.023.
Kaunzner UW, Miller MM, Gottfried-Blackmore A, Gal-Toth J, Felger JC, McEwen BS, et al. Accumulation of resident and peripheral dendritic cells in the aging CNS. Neurobiol Aging. 2012;33(4):681–93 e1. https://doi.org/10.1016/j.neurobiolaging.2010.06.007.
Funding
Y.H., R.F.K., and G.X. were supported by grants NS-096917, NS-106746, NS-112394, and NS-116786. SK was supported by NS-007222 from the National Institutes of Health.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Ethics Approval
All institutional and national guidelines for the care and use of laboratory animals were followed.
Conflict of Interest
Chaoyi Bian, Yingfeng Wan, Sravanthi Koduri, Ya Hua, Richard F. Keep, and Guohua Xi declare no conflict of interests. Guohua Xi is Deputy Editor-in-Chief of Translational Stroke Research.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Bian, C., Wan, Y., Koduri, S. et al. Iron-Induced Hydrocephalus: the Role of Choroid Plexus Stromal Macrophages. Transl. Stroke Res. 14, 238–249 (2023). https://doi.org/10.1007/s12975-022-01031-6
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12975-022-01031-6