Characterization of the role of MIF on retinal health and disease

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Abstract This research focuses on filling gaps in knowledge about the precise molecular pathways that underpin retinal inflammation and impact crosstalk from ischemic retinal diseases, including diabetic retinopathy, vascular diseases, retinopathy of prematurity, and sickle cell retinopathy. Current treatments are often inadequate to prevent vision loss, and adding selective targeting of additional inflammatory mediators may offer new vision-saving therapies. We have identified that (1) the pro- inflammatory cytokine macrophage migration inhibitor factor (MIF) is a druggable target for preventing retinal gliosis and photoreceptor loss in retinal detachment. (2) MIF is up-regulated in the N-methyl-D- aspartic acid (NMDA) damage model which simulates ischemia-mediated retinal excitotoxicity; pharmacologic and genetic inhibition of MIF increases neuronal survival in this model. (3) Clinically we identified a genetic association of MIF promoter polymorphisms with epiretinal membrane formation. Müller glia/astrocytes (MG) are the predominant components of ERM suggesting that MIF could play an important role in the pathological function of retinal glia. MIF inhibitors are in clinical evaluation for a variety of systemic diseases. While inhibition of MIF’s pro-inflammatory effects may indeed underlie the enhanced neuronal survival from MIF d-DT inhibitors, our recent findings strongly suggest that alternative mechanisms also exist. MIF is highly expressed in the Müller glia/astrocytes and it has been hypothesized to be a glial growth factor. Our preliminary data show that conditional inhibition of MIF in the MG enhances the survival of retinal neurons during damage and affects the MG JAK/STAT pathway. Herein, Specific Aim 1 will test the hypothesis that MIF inhibition promotes neuronal survival in retinal damage by activating the gp130/JAK/STAT signaling pathway of Müller glia/astrocytes. In chick and murine NMDA models, we will use pharmacologic and genetic approaches to assess the impact on MG signaling pathways and neuronal survival induced by MIF inhibition. Specific Aim 2 will test the hypothesis that conditional deletion of Müller glia/astrocyte MIF up-regulates the gp130/JAK/STAT pathway and enhances the survival of retinal neurons. In Specific Aim 3 we will develop a single cell RNA-seq database of damaged and undamaged retina treated with MIF inhibitors and/or MG-specific genetic deletion of MIF. We will comprehensively evaluate the transcriptional changes at single-cell resolution in the glia and retinal neurons that result from inhibition of MIF. This research will define the important functional relationships between MIF and signaling pathways on specific cells during retinal damage. The fundamental knowledge gained from understanding the transcriptome ‘switch’ will set the stage for future studies targeting key molecular pathways that are druggable with minimal side effects, but able to prevent and recover visual loss from retinal damage.