Diabetic retinopathy is a ceramidopathy reversible by anti-ceramide immunotherapy Journal Article
| Authors: | Dorweiler, T. F.; Singh, A.; Ganju, A.; Lydic, T. A.; Glazer, L. C.; Kolesnick, R. N.; Busik, J. V. |
| Article Title: | Diabetic retinopathy is a ceramidopathy reversible by anti-ceramide immunotherapy |
| Abstract: | Diabetic retinopathy is a microvascular disease that causes blindness. Using acid sphingomyelinase knockout mice, we reported that ceramide generation is critical for diabetic retinopathy development. Here, in patients with proliferative diabetic retinopathy, we identify vitreous ceramide imbalance with pathologic long-chain C16-ceramides increasing and protective very long-chain C26-ceramides decreasing. C16-ceramides generate pro-inflammatory/pro-apoptotic ceramide-rich platforms on endothelial surfaces. To geo-localize ceramide-rich platforms, we invented a three-dimensional confocal assay and showed that retinopathy-producing cytokines TNFα and IL-1β induce ceramide-rich platform formation on retinal endothelial cells within seconds, with volumes increasing 2-logs, yielding apoptotic death. Anti-ceramide antibodies abolish these events. Furthermore, intravitreal and systemic anti-ceramide antibodies protect from diabetic retinopathy in standardized rodent ischemia reperfusion and streptozotocin models. These data support (1) retinal endothelial ceramide as a diabetic retinopathy treatment target, (2) early-stage therapy of non-proliferative diabetic retinopathy to prevent progression, and (3) systemic diabetic retinopathy treatment; and they characterize diabetic retinopathy as a “ceramidopathy” reversible by anti-ceramide immunotherapy. © 2024 The Author(s) |
| Keywords: | controlled study; nonhuman; animal cell; mouse; animal; metabolism; animals; mice; mice, knockout; apoptosis; interleukin 1beta; animal experiment; animal model; inflammation; drug effect; pathology; mice, inbred c57bl; c57bl mouse; endothelium cell; endothelial cells; immunology; disease severity; immunotherapy; tumor necrosis factor-alpha; rat; cell membrane; ionizing radiation; retina; rats; upregulation; cell nucleus; drug therapy; intercellular adhesion molecule 1; diabetes; single chain fragment variable antibody; knockout mouse; tumor necrosis factor; ceramide; ceramides; cell surface; interleukin-1beta; vitreous body; electrospray mass spectrometry; scanning electron microscopy; retinitis; sphingomyelinase; endothelial cell; retina blood vessel; blood vessel permeability; vitrectomy; experimental diabetes mellitus; diabetes mellitus, experimental; diabetic retinopathy; humans; human; male; female; article; tnfα; acute radiation syndrome; il-1β; nonproliferative diabetic retinopathy; proliferative diabetic retinopathy |
| Journal Title: | Cell Metabolism |
| Volume: | 36 |
| Issue: | 7 |
| ISSN: | 1550-4131 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2024-07-02 |
| Start Page: | 1521 |
| End Page: | 1533.e5 |
| Language: | English |
| DOI: | 10.1016/j.cmet.2024.04.013 |
| PUBMED: | 38718792 |
| PROVIDER: | scopus |
| PMCID: | PMC11222062 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF. Corresponding MSK author is Richard N. Kolesnick -- Source: Scopus |
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