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Colleen M Cebulla, Bongsu Kim, Rania Kusibati, Tyler Heisler-Taylor, Dimosthenis Mantopoulos, Jiaxi Ding, Abhay Satoskar, Jonathan P. Godbout, Sanjoy K Bhattacharya, Mohamed H. Abdel-Rahman; Neuroprotective and anti-gliotic effects of MIF Inhibitor ISO-1 in experimental murine retinal detachment. Invest. Ophthalmol. Vis. Sci. 2017;58(8):5969.
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© ARVO (1962-2015); The Authors (2016-present)
Pro-inflammatory factors promote retinal gliosis and photoreceptor death that underlie vision-threatening complications of retinal detachment (RD). The purpose of this study is to test the hypothesis that inhibition of the pro-inflammatory cytokine macrophage migration inhibitory factor (MIF) blocks photoreceptor apoptosis and retinal gliosis in RD.
RDs were induced by subretinal injection of hyaluronic acid into left eyes of (16-24 week-old) C57BL/6 female mice (n=6-18/group) or BALB/c Mif knockout mice and background controls (n=10/group) under an IACUC-approved protocol. Fellow eyes served as controls. Eyes were enucleated and processed for immunofluorescence and TUNEL analysis. Retinas were isolated for RNA or protein extraction. 8-plex iTRAQ labeled proteomics was performed to evaluated up- and down-regulated proteins in RD compared to controls. ELISA evaluated MIF expression. C57BL/6 mice were treated with daily intraperitoneal injection of MIF inhibitor ISO-1 or vehicle and retinas were evaluated for apoptosis, inflammatory infiltrate, and gliosis.
MIF was up-regulated 1.9-fold in RDs on iTRAQ analysis, which was further corroborated by ELISA (1.7 ± 0.079 ng MIF/µg total protein in controls vs. 1.87±0.138 in RD, *p≤0.089). Upregulated MIF was also detected in subretinal macrophages in RD. ISO-1 (40mg/kg) significantly decreased TUNEL positive photoreceptors in RD ((4125.89 ± 849.5 cells/mm2 retina vehicle vs 588.68 ± 409.5 cells/mm2 retina ISO-1, p=0.003). The density and polarization of macrophages were not altered. Retinal gliosis GFAP expression was reduced by ISO-1 treatment and MIF genetic depletion. Retinal phosphorylated ERK levels were increased in ISO-1 and MIF genetic depletion.
MIF inhibition should be explored as a potential therapeutic adjunct for RD.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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