P38 inhibition reverses TGFβ1 and TNFα-induced contraction in a model of proliferative vitreoretinopathy

Area of Science:

• Ophthalmology
• Cell Biology
• Molecular Biology

Background:

• Proliferative vitreoretinopathy (PVR) involves retinal pigment epithelial (RPE) cell transformation and epiretinal membrane (ERM) contraction, leading to vision loss.
• Transforming growth factor-beta 1 (TGFβ1) and tumor necrosis factor-alpha (TNFα) are implicated in PVR pathogenesis.

Purpose of the Study:

• To investigate the synergistic effects of TGFβ1 and TNFα on adult human RPE (ahRPE) cells.
• To identify molecular pathways involved in cytokine-induced RPE cell transformation and membrane contraction.
• To evaluate the therapeutic potential of targeting the p38-MAPK pathway in PVR.

Main Methods:

• Treatment of ahRPE cells with TGFβ1 and TNFα (TNT).
• Analysis of gene expression using whole transcriptome RNA sequencing on patient-dissected PVR membranes.
• Pharmacological inhibition of the p38-MAPK signaling pathway.

Main Results:

• Synergistic treatment with TGFβ1 and TNFα induced aggressive contraction and motility in ahRPE cells, forming motile membranes.
• TNT-induced membranes uniquely expressed muscle and extracellular rearrangement genes.
• Whole transcriptome analysis of PVR membranes revealed activation of the p38-MAPK pathway.
• p38-MAPK inhibition blocked ahRPE transformation and membrane contraction, and could reverse existing contractility.

Conclusions:

• TGFβ1 and TNFα act synergistically to drive PVR pathogenesis through RPE cell transformation and membrane contraction.
• The p38-MAPK pathway is a critical mediator of TNT-induced RPE cell contractility.
• Targeting the p38-MAPK pathway presents a potential therapeutic strategy for PVR, even after ERM formation.