Abstract
Persistent inflammation is a complication associated with many ocular diseases. Changes in ocular vessels can amplify disease responses and contribute to vision loss by influencing the delivery of leukocytes to the eye, vascular leakage, and perfusion. Here, we report the anti-inflammatory activity for AXT107, a non-RGD, 20-mer αvβ3 and α5β1 integrin-binding peptide that blocks vascular endothelial growth factor (VEGF)-signaling and activates tyrosine kinase with immunoglobulin and EGF-like domains 2 (Tie2) using the normally inhibitory ligand angiopoietin 2 (Ang2). Tumor necrosis factor α (TNFα), a central inflammation mediator, induces Ang2 release from endothelial cells to enhance its stimulation of inflammation and vascular leakage. AXT107 resolves TNFα-induced vascular inflammation in endothelial cells by converting the endogenously released Ang2 into an agonist of Tie2 signaling, thereby disrupting both the synergism between TNFα and Ang2 while also preventing inhibitor of nuclear factor-κB α (IκBα) degradation directly through Tie2 signaling. This recovery of IκBα prevents nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) nuclear localization, thereby blocking NF-κB-induced inflammatory responses, including the production of VCAM-1 and ICAM-1, leukostasis, and vascular leakage in cell and mouse models. AXT107 also decreased the levels of pro-inflammatory TNF receptor 1 (TNFR1) without affecting levels of the more protective TNFR2. These data suggest that AXT107 may provide multiple benefits in the treatment of retinal/choroidal and other vascular diseases by suppressing inflammation and promoting vascular stabilization.
Highlights
Inflammation is an important component and underlying cause of many ocular diseases such as diabetic macular edema (DME), retinal vein occlusion (RVO), diabetic retinopathy (DR), dry and wet age-related macular degeneration (AMD), uveitic glaucoma, macular edema secondary to uveitis, and dry eye disease (DED) [1,2,3,4,5,6]
Western blots of human umbilical vein endothelial cells (HUVECs) treated with 10 ng/mL tumor necrosis factor α (TNFα) showed a clear reduction in inhibitor of nuclear factor-κB α (IκBα) levels consistent with an inflammatory response as early as 30 min, and these reduced levels persisted for 6 h, the last timepoint tested (Figure 1A)
A similar response was observed in Microvascular endothelial cells (MECs), except that IκBα levels at 30 min had already recovered in AXT107-treated cells to the same level observed in MECs that were not treated with TNFα (Figure 1D lane 5 vs. lane 1)
Summary
Inflammation is an important component and underlying cause of many ocular diseases such as diabetic macular edema (DME), retinal vein occlusion (RVO), diabetic retinopathy (DR), dry and wet age-related macular degeneration (AMD), uveitic glaucoma, macular edema secondary to uveitis, and dry eye disease (DED) [1,2,3,4,5,6]. Diseases like DME and wet AMD are successfully treated with anti-vascular endothelial growth factor (VEGF) agents, but many patients still do not see improvements of more than 15 letters when treated with these agents. Chronic use of corticosteroids can cause cataracts and glaucoma while anti-TNFα antibodies can increase patients’ susceptibilities to infectious diseases, cancer, and other complications [8]. Safer alternatives to these agents that can be used chronically with minimal side effects are urgently needed
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