Characterization of the role of MIF on retinal health and disease

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.

Grant Number: 5R01EY032573-05
NIH Institute/Center: NIH
Principal Investigator: Colleen Cebulla