Blockade of TREM-1 prevents vitreoretinal neovascularization in mice with oxygen-induced retinopathy |
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Authors: | Modesto A. Rojas Zu T. Shen Ruth B. Caldwell Alexander B. Sigalov |
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Affiliation: | 1. Vascular Biology Center, Augusta University, Augusta, GA 30912, United States;2. SignaBlok, Inc, P.O. Box 4064, Shrewsbury, MA 01545, United States;3. Charlie Norwood VA Medical Center, Augusta, GA 30904, United States |
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Abstract: | In pathological retinal neovascularization (RNV) disorders, the retina is infiltrated by activated leukocytes and macrophages. Triggering receptor expressed on myeloid cells 1 (TREM-1), an inflammation amplifier, activates monocytes and macrophages and plays an important role in cancer, autoimmune and other inflammation-associated disorders. Hypoxia-inducible TREM-1 is involved in cancer angiogenesis but its role in RNV remains unclear. Here, to close this gap, we evaluated the role of TREM-1 in RNV using a mouse model of oxygen-induced retinopathy (OIR). We found that hypoxia induced overexpression of TREM-1 in the OIR retinas compared to that of the room air group. TREM-1 was observed specifically in areas of pathological RNV, largely colocalizing with macrophage colony-stimulating factor (M-CSF) and CD45- and Iba-1-positive cells. TREM-1 blockade using systemically administered first-in-class ligand-independent TREM-1 inhibitory peptides rationally designed using the signaling chain homooligomerization (SCHOOL) strategy significantly (up to 95%) reduced vitreoretinal neovascularization. The peptides were well-tolerated when formulated into lipopeptide complexes for peptide half-life extension and targeted delivery. TREM-1 inhibition substantially downregulated retinal protein levels of TREM-1 and M-CSF suggesting that TREM-1-dependent suppression of pathological angiogenesis involves M-CSF. Targeting TREM-1 using TREM-1-specific SCHOOL peptide inhibitors represents a novel strategy to treat retinal diseases that are accompanied by neovascularization including retinopathy of prematurity. |
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Keywords: | Triggering receptor expressed on myeloid cells 1 Neovascularization SCHOOL model of cell signaling TREM-1 peptide inhibitors Retinopathy |
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