P38 inhibition reverses TGFβ1 and TNFα-induced contraction in a model of proliferative vitreoretinopathy.
Proliferative vitreoretinopathy (PVR) is a metaplasia in the vitreous of the eye manifested by the transformation of retinal pigment epithelial (RPE) cells and the development of contracting epiretinal membranes (ERM), which lead to retinal detachment and vision loss. While TGFβ1 and TNFα have been associated with PVR, here we show that these cytokines act synergistically to induce an aggressive contraction phenotype on adult human (ah)RPE. Connected RPE detach upon contraction and form motile membranes that recruit more cells. TGFβ1 and TNFα (TNT)-induced contracting membranes uniquely express muscle and extracellular rearrangement genes. Whole transcriptome RNA sequencing of patient-dissected PVR membranes showed activation of the p38-MAPK signaling pathway. Inhibition of p38 during TNT treatment blocks ahRPE transformation and membrane contraction. Furthermore, TNT-induced membrane contractility can be reversed by p38 inhibition after induction. Therefore, targeting the p38-MAPK pathway may have therapeutic benefits for patients with PVR even after the onset of contracting ERMs.
['Schiff|Lauren|L|', 'Boles|Nathan C|NC|', 'Fernandes|Marie|M|', 'Nachmani|Bar|B|', 'Gentile|Ronald|R|', 'Blenkinsop|Timothy A|TA|0000-0002-8095-9937']
D000328:Adult D000368:Aged D000369:Aged, 80 and over D002465:Cell Movement D019773:Epiretinal Membrane D004847:Epithelial Cells D005260:Female D005786:Gene Expression Regulation D006801:Humans D008297:Male D008875:Middle Aged D008954:Models, Biological D061251:Primary Cell Culture D034741:RNA, Small Interfering D012163:Retinal Detachment D055213:Retinal Pigment Epithelium D015398:Signal Transduction D059008:Time-Lapse Imaging D059467:Transcriptome D053773:Transforming Growth Factor beta1 D014409:Tumor Necrosis Factor-alpha D018630:Vitreoretinopathy, Proliferative D014822:Vitreous Body D048051:p38 Mitogen-Activated Protein Kinases
Collective cell migration Mechanisms of disease