The Proinflammatory and Proangiogenic Macrophage Migration Inhibitory Factor Is a Potential Regulator in Proliferative Diabetic Retinopathy.

Ahmed M Abu El-Asrar,Gert De Hertogh,Eef Allegaert,Sofie Struyf,Ghislain Opdenakker,Ajmal Ahmad,Mohammad Mairaj Siddiquei,Jo Van Damme,Alexandra De Zutter,Priscilla W Gikandi

doi:10.3389/fimmu.2019.02752

Abstract

The macrophage migration inhibitory factor (MIF)/CD74 signaling pathway is strongly implicated in inflammation and angiogenesis. We investigated the expression of MIF and its receptor CD74 in proliferative diabetic retinopathy (PDR) to reveal a possible role of this pathway in the pathogenesis of PDR. Levels of MIF, soluble (s)CD74, soluble intercellular adhesion molecule-1 (sICAM-1) and vascular endothelial growth factor (VEGF) were significantly increased in the vitreous from patients with PDR compared to nondiabetic control samples. We detected significant positive correlations between the levels of MIF and the levels of sICAM-1 (r = 0.43; p = 0.001) and VEGF (r = 0.7; p < 0.001). Through immunohistochemical analysis of PDR epiretinal membranes, significant positive correlations were also found between microvessel density (CD31 expression) and the numbers of blood vessels expressing MIF (r = 0.56; p = 0.045) and stromal cells expressing MIF (r = 0.79; p = 0.001) and CD74 (r = 0.59; p = 0.045). Similar to VEGF, MIF was induced in Müller cells cultured under hypoxic conditions and MIF induced phosphorylation of ERK1/2 and VEGF production in Müller cells. Intravitreal administration of MIF in normal rats induced increased retinal vascular permeability and significant upregulation of phospho-ERK1/2, NF-κB, ICAM-1 and vascular cell adhesion molecule-1 expression in the retina. MIF induced migration and proliferation of human retinal microvascular endothelial cells. These results suggest that MIF/CD74 signaling is involved in PDR angiogenesis.

Highlights

Ischemia-induced retinal angiogenesis and excessive deposition of extracellular matrix lead to the formation of fibrovascular membranes at the vitreoretinal interface in proliferative diabetic retinopathy (PDR)
We investigated the expression of migration inhibitory factor (MIF) and CD74 in the ocular microenvironment of patients with PDR and correlated their levels with the angiogenic activity in epiretinal fibrovascular membranes and the vitreous levels of vascular endothelial growth factor (VEGF) and the inflammatory biomarker soluble intercellular adhesion molecule 1
We detected for the first time coexpression of MIF and its receptor CD74 in endothelial cells, leukocytes and myofibroblasts in epiretinal fibrovascular membranes from patients with PDR

Summary

Introduction

Ischemia-induced retinal angiogenesis and excessive deposition of extracellular matrix lead to the formation of fibrovascular membranes at the vitreoretinal interface in proliferative diabetic retinopathy (PDR). This outgrowth of fibrovascular tissue, composed of new blood vessels, leukocytes and α-smooth muscle actin (α-SMA)-expressing myofibroblasts [1,2,3,4], often causes serious vision loss due to recurrent vitreous hemorrhage and/or traction retinal detachment. Several studies support the paradigm that inflammation, neovascularization and fibrosis are critical mechanisms for PDR initiation and progression as the authors showed overexpression of inflammatory, angiogenic and fibrogenic factors inducing those processes [1,2,3,4,5]. A new challenge in PDR research is the identification of the molecular links between inflammation and angiogenesis

Methods

Results

Conclusion