MyD88-Dependent Pathways in Leukocytes Affect the Retina in Diabetes
Open Access
- 11 July 2013
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 8 (7), e68871
- https://doi.org/10.1371/journal.pone.0068871
Abstract
Previous studies by us and other have provided evidence that leukocytes play a critical role in the development of diabetic retinopathy, suggesting a possible role of the innate immune system in development of the retinopathy. Since MyD88 is a convergence point for signaling pathways of the innate immune system (including Toll-Like Receptors (TLRs) and interleukin-1ß (IL-1ß)), the purpose of this study was to assess the role of MyD88 and its dependent pathways on abnormalities that develop in retina and white blood cells related to diabetic retinopathy. C57BL/6J mice were made diabetic with streptozotocin. Chimeric mice were generated in which MyD88-dependent pathways were deleted from bone marrow-derived only. Mice were sacrificed at 2 mos of diabetes for assessment of, leukostasis, albumin accumulation in neural retina, leukocyte-mediated killing of retinal endothelial cells, and cytokine/chemokine generation by retinas of diabetic mice in response to TLR agonists, IL-6 and CXCL1 were generated in retinas from diabetic (but not nondiabetic mice) following incubation with Pam3CysK/TLR2, but incubation with other TLR ligands or IL-1ß did not induce cytokine production in retinas from nondiabetic or diabetic mice. Diabetes-induced abnormalities (leukostasis, ICAM-1 expression on the luminal surface of the vascular endothelium, retinal superoxide generation) were significantly inhibited by removing either MyD88 or the signaling pathways regulated by it (TLRs 2 and 4, and IL-1ß) from bone marrow-derived cells only. Leukocyte-mediated killing of endothelial cells tended to be decreased in the marrow-derived cells lacking TLR2/4, but the killing was significantly exacerbated if the marrow cells lacked MyD88 or the receptor for IL-1ß (IL-1ßr). MyD88-dependent pathways play an important role in the development of diabetes-induced inflammation in the retina, and inhibition of MyD88 might be a novel target to inhibit early abnormalities of diabetic retinopathy and other complications of diabetes.This publication has 18 references indexed in Scilit:
- Leukocytes regulate retinal capillary degeneration in the diabetic mouse via generation of leukotrienesJournal of Leukocyte Biology, 2013
- Increased Synthesis of Leukotrienes in the Mouse Model of Diabetic RetinopathyInvestigative Ophthalmology & Visual Science, 2010
- 5-Lipoxygenase, but Not 12/15-Lipoxygenase, Contributes to Degeneration of Retinal Capillaries in a Mouse Model of Diabetic RetinopathyDiabetes, 2008
- Immunological mechanisms in the pathogenesis of diabetic retinopathySeminars in Immunopathology, 2008
- Signaling to NF-κB by Toll-like receptorsTrends in Molecular Medicine, 2007
- Critical role of inducible nitric oxide synthase in degeneration of retinal capillaries in mice with streptozotocin-induced diabetesDiabetologia, 2007
- Topical Administration of Nepafenac Inhibits Diabetes-Induced Retinal Microvascular Disease and Underlying Abnormalities of Retinal Metabolism and PhysiologyDiabetes, 2007
- Contributions of Inflammatory Processes to the Development of the Early Stages of Diabetic RetinopathyExperimental Diabetes Research, 2007
- A central role for inflammation in the pathogenesis of diabetic retinopathyThe FASEB Journal, 2004
- Isolation and characterization of murine retinal endothelial cells.2003