The modulatory effect of IL11 on retinal angiogenesis

Abstract

Purpose : As a pleiotopic pathway with great angiomodulatory potential, the STAT3 pathway represents an attractive therapeutic target for the treatment of vasoproliferative retinal diseases. IL11, a member of the IL6 cytokine family, is a potent activator of the STAT3 pathway. However, the role of IL11 in the retina is still poorly understood. The aim of this study is to characterize the modulatory effect of IL11 on retinal angiogenesis.

Methods : The concentrations of IL11 and IL11 receptor (IL11R) in human vitreous samples from 16 proliferative diabetic retinopathy (PDR) and 16 control patients were determined by ELISA.
The angiomodulatory effects of VEGF, IL11, soluble IL11R and combinations thereof on human vascular endothelial cells (HUVECs) were determined by spheroid sprouting and migration assays. Transcriptomic shifts were assessed by RNA sequencing.
In the model for oxygen induced retinopathy the retinal vasculature of Bl6/J mice were examined after injection with either IL11, IL11+sIL11R or PBS.
Intracellular signaling pathways in HUVECs and murine Müller cells were studied by Western blot.

Results : While IL11R is significantly upregulated in vitreous samples from PDR patients (ñ=118 pg/mL) compared to the control patients (ñ=1 pg/mL), the concentration of IL-11 showed no significant difference (ñ≈3 pg/mL).
In-vitro, IL11 primarily activated the STAT3 signaling pathway (cis-signaling) and caused a significant reduction of VEGF-induced sprouting in HUVECs (Δ= -15%; p<0.05). Interestingly, the combination of IL11 and sIL11R (trans-signaling) enhanced cell sprouting and migration (Δ= +21.6%; p<0.05). Western blot analyses revealed that IL11 trans-signaling simultaneously activated STAT3 and STAT1 as well as AKT in HUVECs resulting in a significant transcriptomic shift favoring angiogenesis.
In-vivo, IL11 and IL11+sIL11R both led to a significant reduction in retinal neovascularization (N=15; p<0.05). Cryosections of murine eyes after injection suggested that Müller cells respond to IL11 treatment with no differences in intracellular signaling in response to IL11 cis- or trans-signaling.

Conclusions : The different angiogenic properties of IL11 and IL11+sIL11R can be explained by individual signaling responses and associated transcriptomic shifts. The elevated IL11R levels in vitreous samples from PDR patients suggest that IL11 signaling play an important role in PDR pathogenesis, providing an entirely new perspective on its role in angiogenesis.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.