Shima Dehghani, Manuel Chacon, Katayoon Forouzanfar, Seokjoo Lee, Akitomo Narimatsu, Rohan Bir Singh, Aytan Musayeva, Francesca Kahale, Sonia Anchouche, Neda Heydarian, Shilpy Bhullar, Thomas H Dohlman, Yihe Chen, Tomas Blanco, Reza Dana
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引用次数: 0
Abstract
Corneal neovascularization (NV) leads to inflammation and fibrosis, thereby compromising visual acuity and corneal graft survival. Despite existing antiangiogenic therapies, clinical outcomes remain suboptimal. This study explores the antiangiogenic potential of regulatory T cells (Tregs) through programmed death-ligand 1 (PD-L1). In vitro tube formation assays were performed by co-culturing MS1 endothelial cells with Tregs. In addition, murine corneal suture-induced NV and high-risk corneal transplantation models were used to evaluate the effects of subconjunctival Treg injections in vivo. Wild-type (WT) Tregs inhibited endothelial tube formation, whereas PD-L1-/- Tregs failed to exert this effect. Blocking B7-1 on MS1 cells attenuated the inhibitory effect of WT Tregs, indicating a PD-L1-B7-1 interaction as a key mechanism. Furthermore, vascular endothelial growth factor A expression in MS1 cells was significantly reduced on co-culturing with WT Tregs, a response that was absent with PD-L1-/- Tregs. In vivo, subconjunctival Treg injections significantly reduced corneal NV in both corneal suture-induced NV and high-risk corneal transplantation models, and this effect was lost on blocking PD-L1. These results show that PD-L1 expressed by Tregs plays a pivotal role in suppressing corneal angiogenesis, acting through a contact-dependent mechanism through B7-1, leading to down-regulation of vascular endothelial growth factor A, highlighting the function of PD-L1 in Treg modulation of corneal angiogenesis.
期刊介绍:
The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, Inc., seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. Foundational studies that incorporate deep learning and artificial intelligence are also welcome. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches.