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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
First Online:

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

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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.

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© 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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