Chronic exposure to tumor necrosis factor alpha induces retinal pigment epithelium cell dedifferentiation

J Neuroinflammation. 2018 Mar 16;15(1):85. doi: 10.1186/s12974-018-1106-8.


Background: The retinal pigment epithelium (RPE) is a monolayer of pigmented cells with important barrier and immuno-suppressive functions in the eye. We have previously shown that acute stimulation of RPE cells by tumor necrosis factor alpha (TNFα) downregulates the expression of OTX2 (Orthodenticle homeobox 2) and dependent RPE genes. We here investigated the long-term effects of TNFα on RPE cell morphology and key functions in vitro.

Methods: Primary porcine RPE cells were exposed to TNFα (at 0.8, 4, or 20 ng/ml per day) for 10 days. RPE cell morphology, phagocytosis, barrier- and immunosuppressive-functions were assessed.

Results: Chronic (10 days) exposure of primary RPE cells to TNFα increases RPE cell size and polynucleation, decreases visual cycle gene expression, impedes RPE tight-junction organization and transepithelial resistance, and decreases the immunosuppressive capacities of the RPE. TNFα-induced morphological- and transepithelial-resistance changes were prevented by concomitant Transforming Growth Factor β inhibition.

Conclusions: Our results indicate that chronic TNFα-exposure is sufficient to alter RPE morphology and impede cardinal features that define the differentiated state of RPE cells with striking similarities to the alterations that are observed with age in neurodegenerative diseases such as age-related macular degeneration.

Keywords: Age-related macular degeneration; Neurodegenerative disease; Neuroinflammation; Retinal pigment epithelium; Transforming growth factor beta; Tumor necrosis factor alpha.

MeSH terms

  • Actins / metabolism
  • Animals
  • Capillary Resistance / drug effects
  • Cell Differentiation / drug effects*
  • Cell Fusion
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Epithelial Cells / drug effects*
  • Gene Expression Regulation / drug effects
  • Humans
  • Lipopolysaccharides / pharmacology
  • Monocytes / drug effects
  • Monocytes / metabolism
  • Otx Transcription Factors / metabolism*
  • Phagocytosis / drug effects
  • Proto-Oncogene Proteins / metabolism
  • RNA, Messenger / metabolism
  • Retinal Pigment Epithelium / cytology*
  • Rhodopsin / metabolism
  • Trans-Activators / metabolism
  • Tumor Necrosis Factor-alpha / metabolism*
  • Zonula Occludens-1 Protein / metabolism


  • ACTA2 protein, human
  • Actins
  • Lipopolysaccharides
  • OTX2 protein, human
  • Otx Transcription Factors
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • TJP1 protein, human
  • Trans-Activators
  • Tumor Necrosis Factor-alpha
  • Zonula Occludens-1 Protein
  • proto-oncogene protein Spi-1
  • Rhodopsin