The Proinflammatory and Proangiogenic Macrophage Migration Inhibitory Factor Is a Potential Regulator in
Ahmed M Abu El-Asrar1,2, Ajmal Ahmad1, Mohammad Mairaj Siddiquei1
1Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
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.
Insights
Macrophage migration inhibitory factor (MIF) and its receptor CD74 are implicated in proliferative diabetic retinopathy (PDR) angiogenesis. Elevated MIF/CD74 signaling contributes to PDR pathogenesis by promoting neovascularization and vascular permeability.
Area of Science:
- Ophthalmology
- Immunology
- Molecular Biology
Background:
- The macrophage migration inhibitory factor (MIF)/CD74 pathway is linked to inflammation and angiogenesis.
- Proliferative diabetic retinopathy (PDR) involves abnormal blood vessel growth in the retina.
Purpose of the Study:
- To investigate the expression and role of the MIF/CD74 pathway in the pathogenesis of PDR.
- To determine if MIF/CD74 signaling contributes to angiogenesis in PDR.
Main Methods:
- Vitreous fluid analysis from PDR patients and controls for MIF, soluble CD74 (sCD74), soluble intercellular adhesion molecule-1 (sICAM-1), and vascular endothelial growth factor (VEGF).
- Immunohistochemical analysis of PDR epiretinal membranes for microvessel density, MIF, and CD74 expression.
- In vitro studies using Müller cells and human retinal microvascular endothelial cells.
- Intravitreal administration of MIF in normal rats.
Main Results:
- Vitreous levels of MIF, sCD74, sICAM-1, and VEGF were significantly elevated in PDR patients.
- Positive correlations were found between MIF levels and sICAM-1, VEGF, microvessel density, and CD74 expression in PDR tissues.
- MIF induced retinal vascular permeability, inflammation markers (phospho-ERK1/2, NF-κB, ICAM-1), and endothelial cell migration/proliferation in experimental models.
Conclusions:
- The MIF/CD74 signaling pathway plays a significant role in PDR angiogenesis.
- Targeting the MIF/CD74 pathway may offer a therapeutic strategy for PDR.
