Diabetes mediated functional changes in the retina of Müller-glial-cell-specific Il6ra^-/- mice

Abstract

Purpose : Interleukin-6 (IL-6) has been implicated in the pathology of diabetic retinopathy (DR). IL-6 trans-signaling via soluble IL-6 receptor (IL-6R) is primarily responsible for its pro-inflammatory functions, while classical signaling via membrane-bound IL-6R is considered to be anti-inflammatory. Using our Müller-glial-cell-specific Il6ra^-/- (KO) mouse, this study examined the effect of the loss of IL-6 classical signaling in Müller glial cells (MGCs) on the changes in retinal thickness, responsiveness, and vasculature over 9 months of diabetes.

Methods : Diabetes was induced in 6-8 week old KO and C57BL/6J (WT) mice by intraperitoneal injection of streptozotocin (40 mg/kg, 5 days). Functional tests were conducted at 2, 6, and 9 months of diabetes alongside age-matched controls for each strain. Retinal thickness was measured using spectral domain optical coherence tomography (SD-OCT). Electroretinography (ERG) was used to measure a- and b-wave amplitudes (µV) over increasing flash intensities of scotopic and photopic light. Vascular leakage was assessed by fundoscopy and fluorescein angiography. Two-way ANOVA with Tukey’s multiple comparisons was used for statistical analyses (p<0.05).

Results : Total retinal thickness was significantly decreased in KO mice starting at 2 months of diabetes, whereas diabetic WT mice showed total retinal thinning at 6 months. This decrease in diabetic KO mice at each time point corresponded to significant thinning of the retinal inner nuclear layer (INL), the layer containing MGC nuclei. The INL of diabetic KO mice was 14%, 18%, and 25% thinner at 2, 6, and 9 months of diabetes respectively, whereas WT diabetic mice showed no significant change in INL thickness up to 9 months. Similarly, diabetic KO mice showed a significant decrease in scotopic ERG response at 6 months of diabetes relative to their controls, with b-wave amplitudes decreasing by 12-40%.

Conclusions : The loss of IL-6R in KO mice, and a subsequent loss of classical signaling in MGCs in vivo, corresponds to increased severity of pathologic retinal thinning and abnormal ERG response seen in DR. These results support a protective role for IL-6 classical signaling in the diabetic retina, particularly in early-stage DR, and further a rationale for inhibiting only the trans-signaling pathway as a therapeutic for DR.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.