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Lipofuscin-dependent stimulation of microglial cells

  • Martin Dominik Leclaire
  • Gerburg Nettels-Hackert
  • Jeannette König
  • Annika Höhn
  • Tilman Grune
  • Constantin E. Uhlig
  • Uwe Hansen
  • Nicole Eter
  • Peter HeiduschkaEmail author
Basic Science
  • 61 Downloads

Abstract

Purpose

To examine the reaction of microglial cells (MG) when incubated with lipofuscin (LP) in vitro with emphasis on the immunological reaction of the MG toward LP and the suppression of this reaction by immunomodulatory agents. MG are involved in the pathogenesis of degenerative eye disorders such as age-related macular degeneration (AMD). LP is a heterogeneous waste material that accumulates in the retinal pigment epithelium (RPE) cells with advancing age. LP is known to have toxic effects on RPE cells and therefore an elevated LP-derived fundus autofluorescence is a risk factor for AMD development. MG in the subretinal space have been reported in eyes affected by AMD. Moreover, in senescent mice, subretinal MG were found, which display an autofluorescence that may be derived from LP uptake.

Methods

In this study, we incubated MG (BV-2 cell line and primary cells from murine brain) in vitro with LP isolated from the human RPE. We observed phagocytosis, studied cell morphologies, and analyzed the cell culture supernatants. We also investigated the effect of the immunomodulatory agents hydrocortisone (HC), minocycline, and the tripeptide TKP.

Results

The MG phagocytosed the LP quickly and completely. We detected highly elevated levels of pro-inflammatory cytokines (especially of IL-6, IL-23p19, TNF-α, KC, RANTES, and IL-1α) in the cell culture supernatants. Furthermore, levels of vascular endothelial growth factor (VEGF) were raised in BV-2 cells. Anti-inflammatory agents added to the cell cultures inhibited the inflammatory reaction, in particular hydrocortisone (HC). Minocycline and TKP had less impact on the cytokine release.

Conclusion

The interaction of MG and LP could play a role in the development of retinal degeneration by triggering an inflammatory reaction and angiogenesis.

Keywords

Microglia Lipofuscin Age-related macular degeneration Inflammation VEGF Hydrocortisone 

Abbreviations

AMD

Age-related macular degeneration

CNS

Central nervous system

GA

Geographic atrophy

HC

Hydrocortisone

IL

Interleukin

LP

Lipofuscin

MCP

monocyte chemoattractant protein

MG

Microglial cells

MIP

Macrophage inflammatory protein

NO

Nitric oxide

PBS

Phosphate buffered saline

RPE

Retinal pigment epithelium

TNF

Tumor necrosis factor

TKP

Tripeptide (threonine–lysine–proline)

VEGF

Vascular endothelial growth factor

Notes

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

References

  1. 1.
    Resnikoff S, Pascolini D, Etya’ale D et al (2004) Global data on visual impairment in the year 2002. Bull World Health Organ 82:844–851PubMedPubMedCentralGoogle Scholar
  2. 2.
    Terman A, Brunk UT (1998) Lipofuscin: mechanisms of formation and increase with age. APMIS 106:265–276CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Pascolini D, Mariotti SP (2012) Global estimates of visual impairment: 2010. Br J Ophthalmol 96:614–618.  https://doi.org/10.1136/bjophthalmol-2011-300539 CrossRefPubMedGoogle Scholar
  4. 4.
    Klein R, Peto T, Bird A, Vannewkirk MR (2004) The epidemiology of age-related macular degeneration. Am J Ophthalmol 137:486–495.  https://doi.org/10.1016/j.ajo.2003.11.069 CrossRefPubMedGoogle Scholar
  5. 5.
    Coleman HR, Chan C-C, Ferris FL, Chew EY (2008) Age-related macular degeneration. Lancet 372:1835–1845.  https://doi.org/10.1016/S0140-6736(08)61759-6 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Nowak JZ (2006) Age-related macular degeneration (AMD): pathogenesis and therapy. Pharmacol Rep 58:353–363PubMedGoogle Scholar
  7. 7.
    Ma W, Wong WT (2016) Aging changes in retinal microglia and their relevance to age-related retinal disease. In: Rickman CB, LaVail MM, Anderson RE et al (eds) Retinal degenerative diseases. Springer International Publishing, Basel, pp 73–78CrossRefGoogle Scholar
  8. 8.
    Ardeljan D, Chan C-C (2013) Aging is not a disease: distinguishing age-related macular degeneration from aging. Prog Retin Eye Res 37:68–89.  https://doi.org/10.1016/j.preteyeres.2013.07.003 CrossRefPubMedGoogle Scholar
  9. 9.
    Patel M, Chan C-C (2008) Immunopathological aspects of age-related macular degeneration. Semin Immunopathol 30:97–110.  https://doi.org/10.1007/s00281-008-0112-9 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Chen M, Xu H (2015) Parainflammation, chronic inflammation and age-related macular degeneration. J Leukoc Biol 98:713–725.  https://doi.org/10.1189/jlb.3RI0615-239R CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Penfold PL, Provis JM, Furby JH et al (1990) Autoantibodies to retinal astrocytes associated with age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 228:270–274CrossRefPubMedGoogle Scholar
  12. 12.
    Penfold PL, Liew SC, Madigan MC, Provis JM (1997) Modulation of major histocompatibility complex class II expression in retinas with age-related macular degeneration. Invest Ophthalmol Vis Sci 38:2125–2133PubMedGoogle Scholar
  13. 13.
    Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314–1318.  https://doi.org/10.1126/science.1110647 CrossRefGoogle Scholar
  14. 14.
    Davalos D, Grutzendler J, Yang G et al (2005) ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 8:752–758.  https://doi.org/10.1038/nn1472 CrossRefPubMedGoogle Scholar
  15. 15.
    Wake H, Moorhouse AJ, Jinno S et al (2009) Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci 29:3974–3980.  https://doi.org/10.1523/JNEUROSCI.4363-08.2009 CrossRefPubMedGoogle Scholar
  16. 16.
    Raivich G (2005) Like cops on the beat: the active role of resting microglia. Trends Neurosci 28:571–573.  https://doi.org/10.1016/j.tins.2005.09.001 CrossRefPubMedGoogle Scholar
  17. 17.
    Kim SU, de Vellis J (2005) Microglia in health and disease. J Neurosci Res 81:302–313.  https://doi.org/10.1002/jnr.20562 CrossRefPubMedGoogle Scholar
  18. 18.
    Beynon SB, Walker FR (2012) Microglial activation in the injured and healthy brain: what are we really talking about? Practical and theoretical issues associated with the measurement of changes in microglial morphology. Neuroscience 225:162–171.  https://doi.org/10.1016/j.neuroscience.2012.07.029 CrossRefPubMedGoogle Scholar
  19. 19.
    Boche D, Perry VH, Nicoll JAR (2013) Review: activation patterns of microglia and their identification in the human brain. Neuropathol Appl Neurobiol 39:3–18.  https://doi.org/10.1111/nan.12011 CrossRefPubMedGoogle Scholar
  20. 20.
    Raivich G, Bohatschek M, Kloss CU et al (1999) Neuroglial activation repertoire in the injured brain: graded response, molecular mechanisms and cues to physiological function. Brain Res Brain Res Rev 30:77–105CrossRefPubMedGoogle Scholar
  21. 21.
    Streit WJ, Kreutzberg GW (1988) Response of endogenous glial cells to motor neuron degeneration induced by toxic ricin. J Comp Neurol 268:248–263.  https://doi.org/10.1002/cne.902680209 CrossRefPubMedGoogle Scholar
  22. 22.
    Boje KM, Arora PK (1992) Microglial-produced nitric oxide and reactive nitrogen oxides mediate neuronal cell death. Brain Res 587:250–256.  https://doi.org/10.1016/0006-8993(92)91004-X CrossRefPubMedGoogle Scholar
  23. 23.
    Lee YB, Nagai A, Kim SU (2002) Cytokines, chemokines, and cytokine receptors in human microglia. J Neurosci Res 69:94–103.  https://doi.org/10.1002/jnr.10253 CrossRefPubMedGoogle Scholar
  24. 24.
    Salter MW, Stevens B (2017) Microglia emerge as central players in brain disease. Nat Med 23:1018–1027.  https://doi.org/10.1038/nm.4397 CrossRefPubMedGoogle Scholar
  25. 25.
    Karlstetter M, Ebert S, Langmann T (2010) Microglia in the healthy and degenerating retina: insights from novel mouse models. Immunobiology 215:685–691.  https://doi.org/10.1016/j.imbio.2010.05.010 CrossRefPubMedGoogle Scholar
  26. 26.
    Krause TA, Alex AF, Engel DR et al (2014) VEGF-production by CCR2-dependent macrophages contributes to laser-induced choroidal neovascularization. PLoS One 9.  https://doi.org/10.1371/journal.pone.0094313
  27. 27.
    Diaz-Araya CM, Provis JM, Penfold PL, Billson FA (1995) Development of microglial topography in human retina. J Comp Neurol 363:53–68.  https://doi.org/10.1002/cne.903630106 CrossRefPubMedGoogle Scholar
  28. 28.
    Chen L, Yang P, Kijlstra A (2002) Distribution, markers, and functions of retinal microglia. Ocul Immunol Inflamm 10:27–39CrossRefPubMedGoogle Scholar
  29. 29.
    Langmann T (2007) Microglia activation in retinal degeneration. J Leukoc Biol 81:1345–1351.  https://doi.org/10.1189/jlb.0207114 CrossRefPubMedGoogle Scholar
  30. 30.
    Cuenca N, Fernández-Sánchez L, Campello L et al (2014) Cellular responses following retinal injuries and therapeutic approaches for neurodegenerative diseases. Prog Retin Eye Res 43:17–75.  https://doi.org/10.1016/j.preteyeres.2014.07.001 CrossRefPubMedGoogle Scholar
  31. 31.
    Madeira MH, Boia R, Santos PF et al (2015) Contribution of microglia-mediated neuroinflammation to retinal degenerative diseases. Mediat Inflamm 2015:e673090.  https://doi.org/10.1155/2015/673090 CrossRefGoogle Scholar
  32. 32.
    Xu H, Chen M, Manivannan A et al (2008) Age-dependent accumulation of lipofuscin in perivascular and subretinal microglia in experimental mice. Aging Cell 7:58–68.  https://doi.org/10.1111/j.1474-9726.2007.00351.x CrossRefPubMedGoogle Scholar
  33. 33.
    Gupta N, Brown KE, Milam AH (2003) Activated microglia in human retinitis pigmentosa, late-onset retinal degeneration, and age-related macular degeneration. Exp Eye Res 76:463–471.  https://doi.org/10.1016/S0014-4835(02)00332-9 CrossRefPubMedGoogle Scholar
  34. 34.
    Lad EM, Cousins SW, Van Arnam JS, Proia AD (2015) Abundance of infiltrating CD163+ cells in the retina of postmortem eyes with dry and neovascular age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 253:1941–1945.  https://doi.org/10.1007/s00417-015-3094-z CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Strehler BL, Mark DD, Mildvan AS, Gee MV (1959) Rate and magnitude of age pigment accumulation in the human myocardium. J Gerontol 14:430–439.  https://doi.org/10.1093/geronj/14.4.430 CrossRefPubMedGoogle Scholar
  36. 36.
    Reichel W (1968) Lipofuscin pigment accumulation and distribution in five rat organs as a function of age. J Gerontol 23:145–153.  https://doi.org/10.1093/geronj/23.2.145 CrossRefPubMedGoogle Scholar
  37. 37.
    Streeten BW (1961) The sudanophilic granules of the human retinal pigment epithelium. Arch Ophthalmol 66:391–398.  https://doi.org/10.1001/archopht.1961.00960010393017 CrossRefGoogle Scholar
  38. 38.
    Feeney-Burns L, Berman ER, Rothman H (1980) Lipofuscin of human retinal pigment epithelium. Am J Ophthalmol 90:783–791CrossRefPubMedGoogle Scholar
  39. 39.
    Feeney-Burns L, Eldred GE (1983) The fate of the phagosome: conversion to “age pigment” and impact in human retinal pigment epithelium. Trans Ophthalmol Soc U K 103(Pt 4):416–421PubMedGoogle Scholar
  40. 40.
    Wing GL, Blanchard GC, Weiter JJ (1978) The topography and age relationship of lipofuscin concentration in the retinal pigment epithelium. Invest Ophthalmol Vis Sci 17:601–607PubMedGoogle Scholar
  41. 41.
    Boulton M, Docchio F, Dayhaw-Barker P et al (1990) Age-related changes in the morphology, absorption and fluorescence of melanosomes and lipofuscin granules of the retinal pigment epithelium. Vis Res 30:1291–1303.  https://doi.org/10.1016/0042-6989(90)90003-4 CrossRefPubMedGoogle Scholar
  42. 42.
    Feeney-Burns L, Hilderbrand ES, Eldridge S (1984) Aging human RPE: morphometric analysis of macular, equatorial, and peripheral cells. Invest Ophthalmol Vis Sci 25:195–200PubMedGoogle Scholar
  43. 43.
    Katz ML, Drea CM, Eldred GE et al (1986) Influence of early photoreceptor degeneration on lipofuscin in the retinal pigment epithelium. Exp Eye Res 43:561–573.  https://doi.org/10.1016/S0014-4835(86)80023-9 CrossRefPubMedGoogle Scholar
  44. 44.
    Katz ML, Eldred GE (1989) Retinal light damage reduces autofluorescent pigment deposition in the retinal pigment epithelium. Invest Ophthalmol Vis Sci 30:37–43PubMedGoogle Scholar
  45. 45.
    Schutt F, Ueberle B, Schnölzer M et al (2002) Proteome analysis of lipofuscin in human retinal pigment epithelial cells. FEBS Lett 528:217–221.  https://doi.org/10.1016/S0014-5793(02)03312-4 CrossRefPubMedGoogle Scholar
  46. 46.
    Warburton S, Southwick K, Hardman RM et al (2005) Examining the proteins of functional retinal lipofuscin using proteomic analysis as a guide for understanding its origin. Mol Vis 11:1122–1134PubMedGoogle Scholar
  47. 47.
    Eldred GE, Miller GV, Stark WS, Feeney-Burns L (1982) Lipofuscin: resolution of discrepant fluorescence data. Science 216:757–759.  https://doi.org/10.1126/science.7079738 CrossRefPubMedGoogle Scholar
  48. 48.
    Delori FC, Dorey CK, Staurenghi G et al (1995) In vivo fluorescence of the ocular fundus exhibits retinal pigment epithelium lipofuscin characteristics. Invest Ophthalmol Vis Sci 36:718–729PubMedGoogle Scholar
  49. 49.
    Marmorstein AD, Marmorstein LY, Sakaguchi H, Hollyfield JG (2002) Spectral profiling of autofluorescence associated with lipofuscin, Bruch’s membrane, and sub-RPE deposits in normal and AMD eyes. Invest Ophthalmol Vis Sci 43:2435–2441PubMedGoogle Scholar
  50. 50.
    Eldred GE, Katz ML (1988) Fluorophores of the human retinal pigment epithelium: separation and spectral characterization. Exp Eye Res 47:71–86.  https://doi.org/10.1016/0014-4835(88)90025-5 CrossRefPubMedGoogle Scholar
  51. 51.
    Wassell J, Davies S, Bardsley W, Boulton M (1999) The photoreactivity of the retinal age pigment lipofuscin. J Biol Chem 274:23828–23832.  https://doi.org/10.1074/jbc.274.34.23828 CrossRefPubMedGoogle Scholar
  52. 52.
    Boulton M, Dontsov A, Jarvis-Evans J et al (1993) Lipofuscin is a photoinducible free radical generator. J Photochem Photobiol B 19:201–204.  https://doi.org/10.1016/1011-1344(93)87085-2 CrossRefPubMedGoogle Scholar
  53. 53.
    Rózanowska M, Jarvis-Evans J, Korytowski W et al (1995) Blue light-induced reactivity of retinal age pigment. In vitro generation of oxygen-reactive species. J Biol Chem 270:18825–18830.  https://doi.org/10.1074/jbc.270.32.18825 CrossRefPubMedGoogle Scholar
  54. 54.
    Gaillard ER, Atherton SJ, Eldred G, Dillon J (1995) Photophysical studies on human retinal lipofuscin. Photochem Photobiol 61:448–453.  https://doi.org/10.1111/j.1751-1097.1995.tb02343.x CrossRefPubMedGoogle Scholar
  55. 55.
    Davies S, Elliott MH, Floor E et al (2001) Photocytotoxicity of lipofuscin in human retinal pigment epithelial cells. Free Radic Biol Med 31:256–265.  https://doi.org/10.1016/S0891-5849(01)00582-2 CrossRefPubMedGoogle Scholar
  56. 56.
    Mohr LKM, Hoffmann AV, Brandstetter C et al (2015) Effects of inflammasome activation on secretion of inflammatory cytokines and vascular endothelial growth factor by retinal pigment epithelial cells. Invest Opthalmol Vis Sci 56:6404.  https://doi.org/10.1167/iovs.15-16898 CrossRefGoogle Scholar
  57. 57.
    Tseng WA, Thein T, Kinnunen K et al (2013) NLRP3 Inflammasome activation in retinal pigment epithelial cells by lysosomal destabilization: implications for age-related macular degeneration. Invest Ophthalmol Vis Sci 54:110–120.  https://doi.org/10.1167/iovs.12-10655 CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Kinnunen K, Petrovski G, Moe MC et al (2012) Molecular mechanisms of retinal pigment epithelium damage and development of age-related macular degeneration. Acta Ophthalmol 90:299–309.  https://doi.org/10.1111/j.1755-3768.2011.02179.x CrossRefPubMedGoogle Scholar
  59. 59.
    Ach T, Huisingh C, McGwin G et al (2014) Quantitative autofluorescence and cell density maps of the human retinal pigment epithelium. Invest Ophthalmol Vis Sci 55:4832–4841.  https://doi.org/10.1167/iovs.14-14802 CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Winkler BS, Boulton ME, Gottsch JD, Sternberg P (1999) Oxidative damage and age-related macular degeneration. Mol Vis 5(32)Google Scholar
  61. 61.
    Rudolf M, Vogt SD, Curcio CA et al (2013) Histologic basis of variations in retinal pigment epithelium autofluorescence in eyes with geographic atrophy. Ophthalmology 120:821–828.  https://doi.org/10.1016/j.ophtha.2012.10.007 CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Zanzottera EC, Ach T, Huisingh C et al (2016) Visualizing retinal pigment epithelium phenotypes in the transition to geographic atrophy in age-related macular degeneration. Retina 36:S12–S25.  https://doi.org/10.1097/IAE.0000000000001276 CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Schmitz-Valckenberg S, Fleckenstein M, Scholl HPN, Holz FG (2009) Fundus autofluorescence and progression of age-related macular degeneration. Surv Ophthalmol 54:96–117.  https://doi.org/10.1016/j.survophthal.2008.10.004 CrossRefPubMedGoogle Scholar
  64. 64.
    Curcio CA, Medeiros NE, Millican CL (1996) Photoreceptor loss in age-related macular degeneration. Invest Ophthalmol Vis Sci 37:1236–1249PubMedGoogle Scholar
  65. 65.
    Dorey CK, Wu G, Ebenstein D et al (1989) Cell loss in the aging retina. Relationship to lipofuscin accumulation and macular degeneration. Invest Ophthalmol Vis Sci 30:1691–1699PubMedGoogle Scholar
  66. 66.
    Wu L, Nagasaki T, Sparrow JR (2010) Chapter 61: photoreceptor cell degeneration in Abcr−/− mice. Adv Exp Med Biol 664:533–539.  https://doi.org/10.1007/978-1-4419-1399-9_61 CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Curcio CA, Millican CL, Allen KA, Kalina RE (1993) Aging of the human photoreceptor mosaic: evidence for selective vulnerability of rods in central retina. Invest Ophthalmol Vis Sci 34:3278–3296PubMedGoogle Scholar
  68. 68.
    Mata NL, Lichter JB, Vogel R et al (2013) Investigation of oral fenretinide for treatment of geographic atrophy in age-related macular degeneration. RETINA 33:498.  https://doi.org/10.1097/IAE.0b013e318265801d CrossRefPubMedGoogle Scholar
  69. 69.
    Rosenfeld PJ, Dugel PU, Holz FG et al (2018) Emixustat hydrochloride for geographic atrophy secondary to age-related macular degeneration: a randomized clinical trial. Ophthalmology 125:1556–1567.  https://doi.org/10.1016/j.ophtha.2018.03.059 CrossRefPubMedGoogle Scholar
  70. 70.
    Blasi E, Barluzzi R, Bocchini V et al (1990) Immortalization of murine microglial cells by a v-raf/v-myc carrying retrovirus. J Neuroimmunol 27:229–237.  https://doi.org/10.1016/0165-5728(90)90073-V CrossRefPubMedGoogle Scholar
  71. 71.
    Bocchini V, Mazzolla R, Barluzzi R et al (1992) An immortalized cell line expresses properties of activated microglial cells. J Neurosci Res 31:616–621.  https://doi.org/10.1002/jnr.490310405 CrossRefPubMedGoogle Scholar
  72. 72.
    Orihuela R, McPherson CA, Harry GJ (2016) Microglial M1/M2 polarization and metabolic states. Br J Pharmacol 173:649–665.  https://doi.org/10.1111/bph.13139 CrossRefPubMedGoogle Scholar
  73. 73.
    Dulla YAT, Kurauchi Y, Hisatsune A et al (2016) Regulatory mechanisms of vitamin D3 on production of nitric oxide and pro-inflammatory cytokines in microglial BV-2 cells. Neurochem Res 41:2848–2858.  https://doi.org/10.1007/s11064-016-2000-3 CrossRefPubMedGoogle Scholar
  74. 74.
    Boulton M, Marshall J (1985) Repigmentation of human retinal pigment epithelial cells in vitro. Exp Eye Res 41:209–218.  https://doi.org/10.1016/0014-4835(85)90026-0 CrossRefPubMedGoogle Scholar
  75. 75.
    Ottis P, Koppe K, Onisko B et al (2012) Human and rat brain lipofuscin proteome. Proteomics 12:2445–2454.  https://doi.org/10.1002/pmic.201100668 CrossRefPubMedGoogle Scholar
  76. 76.
    Ng K-P, Gugiu B, Renganathan K et al (2008) Retinal pigment epithelium lipofuscin proteomics. Mol Cell Proteomics 7:1397–1405.  https://doi.org/10.1074/mcp.M700525-MCP200 CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Yoon KD, Yamamoto K, Ueda K et al (2012) A novel source of methylglyoxal and glyoxal in retina: implications for age-related macular degeneration. PLoS One 7:e41309.  https://doi.org/10.1371/journal.pone.0041309 CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Yin DZ (1992) Lipofuscin-like fluorophores can result from reactions between oxidized ascorbic acid and glutamine. Carbonyl-protein cross-linking may represent a common reaction in oxygen radical and glycosylation-related ageing processes. Mech Ageing Dev 62:35–45CrossRefPubMedGoogle Scholar
  79. 79.
    Schindelin J, Rueden CT, Hiner MC, Eliceiri KW (2015) The ImageJ ecosystem: an open platform for biomedical image analysis. ResearchGate 82:518–529.  https://doi.org/10.1002/mrd.22489 CrossRefGoogle Scholar
  80. 80.
    Kaluzny J, Purta P, Poskin Z et al (2016) Ex vivo confocal spectroscopy of autofluorescence in age-related macular degeneration. PLoS One 11:e0162869.  https://doi.org/10.1371/journal.pone.0162869 CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Brunk UT, Terman A (2002) Lipofuscin: mechanisms of age-related accumulation and influence on cell function. Free Radic Biol Med 33:611–619.  https://doi.org/10.1016/S0891-5849(02)00959-0 CrossRefPubMedGoogle Scholar
  82. 82.
    Feeney L (1978) Lipofuscin and melanin of human retinal pigment epithelium. Fluorescence, enzyme cytochemical, and ultrastructural studies. Invest Ophthalmol Vis Sci 17:583–600PubMedGoogle Scholar
  83. 83.
    Lei L, Tzekov R, Tang S, Kaushal S (2012) Accumulation and autofluorescence of phagocytized rod outer segment material in macrophages and microglial cells. Mol Vis 18:103–113PubMedPubMedCentralGoogle Scholar
  84. 84.
    Terman A, Brunk UT (1998) On the degradability and exocytosis of ceroid/lipofuscin in cultured rat cardiac myocytes. Mech Ageing Dev 100:145–156.  https://doi.org/10.1016/S0047-6374(97)00129-2 CrossRefPubMedGoogle Scholar
  85. 85.
    Julien S, Schraermeyer U (2012) Lipofuscin can be eliminated from the retinal pigment epithelium of monkeys. Neurobiol Aging 33:2390–2397.  https://doi.org/10.1016/j.neurobiolaging.2011.12.009 CrossRefPubMedGoogle Scholar
  86. 86.
    Ach T, Tolstik E, Messinger JD et al (2015) Lipofuscin redistribution and loss accompanied by cytoskeletal stress in retinal pigment epithelium of eyes with age-related macular degeneration. Invest Ophthalmol Vis Sci 56:3242–3252.  https://doi.org/10.1167/iovs.14-16274 CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    von Rückmann A, Fitzke FW, Bird AC (1997) Fundus autofluorescence in age-related macular disease imaged with a laser scanning ophthalmoscope. Invest Ophthalmol Vis Sci 38:478–486Google Scholar
  88. 88.
    Rodríguez A, Webster P, Ortego J, Andrews NW (1997) Lysosomes behave as Ca2+-regulated exocytic vesicles in fibroblasts and epithelial cells. J Cell Biol 137:93–104.  https://doi.org/10.1083/jcb.137.1.93 CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Peters S, Reinthal E, Blitgen-Heinecke P et al (2006) Inhibition of lysosomal degradation in retinal pigment epithelium cells induces exocytosis of phagocytic residual material at the basolateral plasma membrane. ResearchGate 38:83–88.  https://doi.org/10.1159/000090268 CrossRefGoogle Scholar
  90. 90.
    Toops KA, Lakkaraju A (2013) Let’s play a game of chutes and ladders. Commun Integr Biol 6.  https://doi.org/10.4161/cib.24474
  91. 91.
    Butovsky O, Jedrychowski MP, Moore CS et al (2014) Identification of a unique TGF-β-dependent molecular and functional signature in microglia. Nat Neurosci 17:131–143.  https://doi.org/10.1038/nn.3599 CrossRefPubMedGoogle Scholar
  92. 92.
    Horvath RJ, Nutile-McMenemy N, Alkaitis MS, De Leo JA (2008) Differential migration, LPS-induced cytokine, chemokine and NO expression in immortalized BV-2 and HAPI cell lines and primary microglial cultures. J Neurochem 107:557–569.  https://doi.org/10.1111/j.1471-4159.2008.05633.x CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Grey AC, Crouch RK, Koutalos Y et al (2011) Spatial localization of A2E in the retinal pigment epithelium. Invest Ophthalmol Vis Sci 52:3926–3933.  https://doi.org/10.1167/iovs.10-7020 CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Eldred GE, Lasky MR (1993) Retinal age pigments generated by self-assembling lysosomotropic detergents. Nature 361:724–726.  https://doi.org/10.1038/361724a0 CrossRefPubMedGoogle Scholar
  95. 95.
    Ablonczy Z, Higbee D, Grey AC et al (2013) Similar molecules spatially correlate with lipofuscin and N-retinylidene-N-retinylethanolamine in the mouse but not in the human retinal pigment epithelium. Arch Biochem Biophys 539:196–202.  https://doi.org/10.1016/j.abb.2013.08.005 CrossRefPubMedGoogle Scholar
  96. 96.
    Ablonczy Z, Higbee D, Anderson DM et al (2013) Lack of correlation between the spatial distribution of A2E and lipofuscin fluorescence in the human retinal pigment epithelium. Invest Ophthalmol Vis Sci 54:5535–5542.  https://doi.org/10.1167/iovs.13-12250 CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Smith RT, Bernstein PS, Curcio CA (2013) Rethinking A2E. Invest Ophthalmol Vis Sci 54:5543.  https://doi.org/10.1167/iovs.13-12798 CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Sparrow JR, Dowling JE, Bok D (2013) Understanding RPE lipofuscin. Invest Ophthalmol Vis Sci 54:8325–8326.  https://doi.org/10.1167/iovs.13-13214 CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Ma W, Coon S, Zhao L et al (2013) A2E accumulation influences retinal microglial activation and complement regulation. Neurobiol Aging 34:943–960.  https://doi.org/10.1016/j.neurobiolaging.2012.06.010 CrossRefPubMedGoogle Scholar
  100. 100.
    Ransohoff RM, Cardona AE (2010) The myeloid cells of the central nervous system parenchyma. Nature 468:253–262.  https://doi.org/10.1038/nature09615 CrossRefPubMedGoogle Scholar
  101. 101.
    Suzumura A, Marunouchi T, Yamamoto H (1991) Morphological transformation of microglia in vitro. Brain Res 545:301–306.  https://doi.org/10.1016/0006-8993(91)91302-H CrossRefPubMedGoogle Scholar
  102. 102.
    Heiduschka P, Thanos S (2006) Cortisol promotes survival and regeneration of axotomised retinal ganglion cells and enhances effects of aurintricarboxylic acid. Graefes Arch Clin Exp Ophthalmol 244:1512–1521.  https://doi.org/10.1007/s00417-005-0164-7 CrossRefPubMedGoogle Scholar
  103. 103.
    Tanaka J, Fujita H, Matsuda S et al (1997) Glucocorticoid- and mineralocorticoid receptors in microglial cells: the two receptors mediate differential effects of corticosteroids. Glia 20:23–37CrossRefPubMedGoogle Scholar
  104. 104.
    Adams AC, Kyle M, Beaman-Hall CM et al (2015) Microglia in glia–neuron co-cultures exhibit robust phagocytic activity without concomitant inflammation or cytotoxicity. Cell Mol Neurobiol 35:961–975.  https://doi.org/10.1007/s10571-015-0191-9 CrossRefPubMedGoogle Scholar
  105. 105.
    Burm SM, Zuiderwijk-Sick EA, Jong AEJ ‘t et al (2015) Inflammasome-induced IL-1β secretion in microglia is characterized by delayed kinetics and is only partially dependent on inflammatory caspases. J Neurosci 35:678–687.  https://doi.org/10.1523/JNEUROSCI.2510-14.2015 CrossRefPubMedGoogle Scholar
  106. 106.
    Tarallo V, Hirano Y, Gelfand BD et al (2012) DICER1 loss and Alu RNA induce age-related macular degeneration via the NLRP3 Inflammasome and MyD88. Cell 149:847–859.  https://doi.org/10.1016/j.cell.2012.03.036 CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Sadda SR, Wu Z, Walsh AC et al (2006) Errors in retinal thickness measurements obtained by optical coherence tomography. Ophthalmology 113:285–293.  https://doi.org/10.1016/j.ophtha.2005.10.005 CrossRefPubMedGoogle Scholar
  108. 108.
    Rezar-Dreindl S, Sacu S, Eibenberger K et al (2016) The intraocular cytokine profile and therapeutic response in persistent neovascular age-related macular degeneration. Invest Opthalmol Vis Sci 57:4144.  https://doi.org/10.1167/iovs.16-19772 CrossRefGoogle Scholar
  109. 109.
    Theodossiadis PG, Liarakos VS, Sfikakis PP et al (2009) Intravitreal administration of the anti-tumor necrosis factor agent infliximab for neovascular age-related macular degeneration. Am J Ophthalmol 147:825–830.  https://doi.org/10.1016/j.ajo.2008.12.004 CrossRefPubMedGoogle Scholar
  110. 110.
    Kauppinen A, Paterno JJ, Blasiak J et al (2016) Inflammation and its role in age-related macular degeneration. Cell Mol Life Sci:1–22.  https://doi.org/10.1007/s00018-016-2147-8
  111. 111.
    Luheshi NM, Kovács KJ, Lopez-Castejon G et al (2011) Interleukin-1α expression precedes IL-1β after ischemic brain injury and is localised to areas of focal neuronal loss and penumbral tissues. J Neuroinflammation 8:186.  https://doi.org/10.1186/1742-2094-8-186 CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Zhao M, Bai Y, Xie W et al (2015) Interleukin-1β level is increased in vitreous of patients with neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV). PLoS One 10:e0125150.  https://doi.org/10.1371/journal.pone.0125150 CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Pożarowska D, Pożarowski P (2016) The era of anti-vascular endothelial growth factor (VEGF) drugs in ophthalmology, VEGF and anti-VEGF therapy. Cent-Eur J Immunol 41:311–316.  https://doi.org/10.5114/ceji.2016.63132 CrossRefPubMedPubMedCentralGoogle Scholar
  114. 114.
    Aiello LP, Avery RL, Arrigg PG et al (1994) Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 331:1480–1487.  https://doi.org/10.1056/NEJM199412013312203 CrossRefPubMedGoogle Scholar
  115. 115.
    Bahadorani S, Singer M (2017) Recent advances in the management and understanding of macular degeneration. F1000Research 6:519.  https://doi.org/10.12688/f1000research.10998.1 CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Liu J, Copland DA, Horie S et al (2013) Myeloid cells expressing VEGF and Arginase-1 following uptake of damaged retinal pigment epithelium suggests potential mechanism that drives the onset of choroidal angiogenesis in mice. PLoS One 8:e72935.  https://doi.org/10.1371/journal.pone.0072935 CrossRefPubMedPubMedCentralGoogle Scholar
  117. 117.
    Checchin D, Sennlaub F, Levavasseur E et al (2006) Potential role of microglia in retinal blood vessel formation. Invest Opthalmol Vis Sci 47:3595.  https://doi.org/10.1167/iovs.05-1522 CrossRefGoogle Scholar
  118. 118.
    Li L, Heiduschka P, Alex AF et al (2017) Behaviour of CD11b-positive cells in an animal model of laser-induced choroidal neovascularisation. Ophthalmologica 237:29–41.  https://doi.org/10.1159/000453550 CrossRefPubMedGoogle Scholar
  119. 119.
    Combadière C, Feumi C, Raoul W et al (2007) CX3CR1-dependent subretinal microglia cell accumulation is associated with cardinal features of age-related macular degeneration. J Clin Invest 117:2920–2928.  https://doi.org/10.1172/JCI31692 CrossRefPubMedPubMedCentralGoogle Scholar
  120. 120.
    Drew PD, Chavis JA (2000) Inhibition of microglial cell activation by cortisol. Brain Res Bull 52:391–396.  https://doi.org/10.1016/S0361-9230(00)00275-6 CrossRefPubMedGoogle Scholar
  121. 121.
    Chang JY, Liu LZ (2000) Inhibition of microglial nitric oxide production by hydrocortisone and glucocorticoid precursors. Neurochem Res 25:903–908CrossRefPubMedGoogle Scholar
  122. 122.
    Ganter S, Northoff H, Männel D, Gebicke-Härter PJ (1992) Growth control of cultured microglia. J Neurosci Res 33:218–230.  https://doi.org/10.1002/jnr.490330205 CrossRefPubMedGoogle Scholar
  123. 123.
    Calvo P, Ferreras A, Adel FA et al (2015) Dexamethasone intravitreal implant as adjunct therapy for patients with wet age-related macular degeneration with incomplete response to ranibizumab. Br J Ophthalmol 99:723–726.  https://doi.org/10.1136/bjophthalmol-2014-305684 CrossRefPubMedGoogle Scholar
  124. 124.
    Ranson NT, Danis RP, Ciulla TA, Pratt L (2002) Intravitreal triamcinolone in subfoveal recurrence of choroidal neovascularisation after laser treatment in macular degeneration. Br J Ophthalmol 86:527–529CrossRefPubMedPubMedCentralGoogle Scholar
  125. 125.
    Edelman JL, Castro MR (2000) Quantitative image analysis of laser-induced choroidal neovascularization in rat. Exp Eye Res 71:523–533.  https://doi.org/10.1006/exer.2000.0907 CrossRefPubMedGoogle Scholar
  126. 126.
    Möller T, Bard F, Bhattacharya A et al (2016) Critical data-based re-evaluation of minocycline as a putative specific microglia inhibitor. Glia 64:1788–1794.  https://doi.org/10.1002/glia.23007 CrossRefPubMedGoogle Scholar
  127. 127.
    Emmetsberger J, Tsirka SE (2012) Microglial inhibitory factor (MIF/TKP) mitigates secondary damage following spinal cord injury. Neurobiol Dis 47:295–309.  https://doi.org/10.1016/j.nbd.2012.05.001 CrossRefPubMedGoogle Scholar
  128. 128.
    Thanos S, Mey J, Wild M (1993) Treatment of the adult retina with microglia-suppressing factors retards axotomy-induced neuronal degradation and enhances axonal regeneration in vivo and in vitro. J Neurosci 13:455–466CrossRefPubMedGoogle Scholar
  129. 129.
    Bhasin M, Wu M, Tsirka SE (2007) Modulation of microglial/macrophage activation by macrophage inhibitory factor (TKP) or tuftsin (TKPR) attenuates the disease course of experimental autoimmune encephalomyelitis. BMC Immunol 8:10.  https://doi.org/10.1186/1471-2172-8-10 CrossRefPubMedPubMedCentralGoogle Scholar
  130. 130.
    Wang Y, Wang VM, Chan C-C (2011) The role of anti-inflammatory agents in age-related macular degeneration (AMD) treatment. Eye 25:127–139.  https://doi.org/10.1038/eye.2010.196 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Martin Dominik Leclaire
    • 1
  • Gerburg Nettels-Hackert
    • 1
  • Jeannette König
    • 2
  • Annika Höhn
    • 2
  • Tilman Grune
    • 2
  • Constantin E. Uhlig
    • 3
  • Uwe Hansen
    • 4
  • Nicole Eter
    • 1
  • Peter Heiduschka
    • 1
    Email author
  1. 1.Research Laboratory, Department of OphthalmologyUniversity Medical CenterMünsterGermany
  2. 2.German Institute of Human NutritionPotsdam-RehbrückeGermany
  3. 3.Cornea Bank Münster, Department of OphthalmologyUniversity Medical CenterMünsterGermany
  4. 4.Institute of Experimental Musculoskeletal Medicine, Medical FacultyUniversity of MünsterMünsterGermany

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