2. Academic Validation
  3. CD40 Ligand-CD40 Interaction Is an Intermediary between Inflammation and Angiogenesis in Proliferative Diabetic Retinopathy

CD40 Ligand-CD40 Interaction Is an Intermediary between Inflammation and Angiogenesis in Proliferative Diabetic Retinopathy

  • Int J Mol Sci. 2023 Oct 25;24(21):15582. doi: 10.3390/ijms242115582.
Ahmed M Abu El-Asrar 1 2,  Mohd I Nawaz 1,  Ajmal Ahmad 1,  Luna Dillemans 3,  Mairaj Siddiquei 1,  Eef Allegaert 4 5,  Priscilla W Gikandi 1,  Gert De Hertogh 4 5,  Ghislain Opdenakker 1 5 6,  Sofie Struyf 3
Affiliations

Affiliations

  • 1 Department of Ophthalmology, College of Medicine, King Saud University, Riyadh 11411, Saudi Arabia.
  • 2 Dr. Nasser Al-Rashid Research Chair in Ophthalmology, College of Medicine, King Saud University, Riyadh 11411, Saudi Arabia.
  • 3 Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute, University of Leuven, 3000 Leuven, Belgium.
  • 4 Laboratory of Histochemistry and Cytochemistry, University of Leuven, 3000 Leuven, Belgium.
  • 5 University Hospitals UZ Gasthuisberg, 3000 Leuven, Belgium.
  • 6 Laboratory of Immunobiology, Department of Microbiology, Immunology and Transplantation, Rega Institute, University of Leuven, 3000 Leuven, Belgium.
PMID: 37958563 DOI: 10.3390/ijms242115582
Abstract

We aimed to investigate the role of the CD40-CD40 ligand (CD40L) pathway in inflammation-mediated angiogenesis in proliferative diabetic retinopathy (PDR). We analyzed vitreous fluids and epiretinal fibrovascular membranes from PDR and nondiabetic patients, cultures of human retinal microvascular endothelial cells (HRMECs) and Müller glial cells and rat retinas with ELISA, immunohistochemistry, flow cytometry and Western blot analysis. Functional tests included measurement of blood-retinal barrier breakdown, in vitro angiogenesis and assessment of monocyte-HRMEC adherence. CD40L and CD40 levels were significantly increased in PDR vitreous samples. We demonstrated CD40L and CD40 expression in vascular endothelial cells, leukocytes and myofibroblasts in epiretinal membranes. Intravitreal administration of soluble (s)CD40L in normal rats significantly increased retinal vascular permeability and induced significant upregulation of phospho-ERK1/2, VEGF, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). sCD40L induced upregulation of VEGF, MMP-9, MCP-1 and HMGB1 in cultured Müller cells and phospo-ERK1/2, p65 subunit of NF-ĸB, VCAM-1 and VEGF in cultured HRMECS. TNF-α induced significant upregulation of CD40 in HRMECs and Müller cells and VEGF induced significant upregulation of CD40 in HRMECs. sCD40L induced proliferation and migration of HRMECs. We provide experimental evidence supporting the involvement of the CD40L-CD40 pathway and how it regulates inflammatory angiogenesis in PDR.

Keywords

CD40 ligand; angiogenesis; endothelial cells; inflammation; proliferative diabetic retinopathy.

Figures
Products