Nuclear factor of activated T-cells (NFAT) regulation of IL-1β-induced retinal vascular inflammation
| Autor: | Garrett Winkler, Meredith J. Giblin, Minjae J. Kim, Gary W. McCollum, Hannah A. Pendergrass, Taylor E. Smith, Megan E. Capozzi, Rong Yang, John S. Penn |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Vascular Endothelial Growth Factor A
Chemokine Leukocyte adhesion molecule Calcineurin Inhibitors Ependymoglial Cells Interleukin-1beta Inflammation Vascular permeability Retina Article Proinflammatory cytokine chemistry.chemical_compound medicine Humans Molecular Biology Chemokine CCL5 Cells Cultured Chemokine CCL2 Retinal Vasculitis Diabetic Retinopathy biology NFATC Transcription Factors Tumor Necrosis Factor-alpha Endothelial Cells Retinal Vessels NFAT Retinal Intercellular Adhesion Molecule-1 chemistry Gene Expression Regulation Cancer research biology.protein Molecular Medicine Tumor necrosis factor alpha medicine.symptom E-Selectin |
| Zdroj: | Biochim Biophys Acta Mol Basis Dis |
| ISSN: | 1879-260X |
| Popis: | Chronic low-grade retinal inflammation is an essential contributor to the pathogenesis of diabetic retinopathy (DR). It is characterized by increased retinal cell expression and secretion of a variety of inflammatory cytokines; among these, IL-1β has the reputation of being a major driver of cytokine-induced inflammation. IL-1β and other cytokines drive inflammatory changes that cause damage to retinal cells, leading to the hallmark vascular lesions of DR; these include increased leukocyte adherence, vascular permeability, and capillary cell death. Nuclear factor of activated T-cells (NFAT) is a transcriptional regulator of inflammatory cytokines and adhesion molecules and is expressed in retinal cells. Consequently, it may influence multiple pathogenic steps early in DR. We investigated the NFAT-dependency of IL-1β-induced inflammation in human Muller cells (hMC) and human retinal microvascular endothelial cells (hRMEC). Our results show that an NFAT inhibitor, Inhibitor of NFAT-Calcineurin Association-6 (INCA-6), decreased IL-1β-induced expression of IL-1β and TNFα in hMC, while having no effect on VEGF, CCL2, or CCL5 expression. We also demonstrate that INCA-6 attenuated IL-1β-induced increases of IL-1β, TNFα, IL-6, CCL2, and CCL5 (inflammatory cytokines and chemokines), and ICAM-1 and E-selectin (leukocyte adhesion molecules) expression in hRMEC. INCA-6 similarly inhibited IL-1β-induced increases in leukocyte adhesion in both hRMEC monolayers in vitro and an acute model of retinal inflammation in vivo. Finally, INCA-6 rescued IL-1β-induced permeability in both hRMEC monolayers in vitro and an acute model of retinal inflammation in vivo. Taken together, these data demonstrate the potential of NFAT inhibition to mitigate retinal inflammation secondary to diabetes. |
| Databáze: | OpenAIRE |
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