TY - JOUR
T1 - P38 inhibition reverses TGFβ1 and TNFα-induced contraction in a model of proliferative vitreoretinopathy
AU - Schiff, Lauren
AU - Boles, Nathan C.
AU - Fernandes, Marie
AU - Nachmani, Bar
AU - Gentile, Ronald
AU - Blenkinsop, Timothy A.
N1 - Funding Information:
First and foremost, we thank the eye donors and their families for the generous donation of retinal tissue. Additionally, we thank Dr. Antonio Marzio at NYU for his help with Western Blot analysis. We would also like to thank Jesse Gelles-Hurwitz for his expertise in the wound healing scratch assay. This study was supported by seed funding from Icahn School of Medicine at Mount Sinai.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85071231353&partnerID=8YFLogxK
U2 - 10.1038/s42003-019-0406-6
DO - 10.1038/s42003-019-0406-6
M3 - Article
C2 - 31069271
AN - SCOPUS:85071231353
SN - 2399-3642
VL - 2
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 162
ER -