Myeloid cell protein tyrosine phosphatase 1B (PTP1B) drives retinal neurodegeneration in diabetic mice
Ali, A.; Boyne, M.; Othman, A.; Kamli-Salino, S.; Kuffova, L.; Forrester, J. V.; Delibegovic, M.
Show abstract
Diabetic retinopathy (DR) is the leading cause of vision loss in the working age population with public health economic implications worldwide. Systemic inflammation and leukocyte activation are early events in diabetes, while microglial activation, neuroinflammation, and retinal neurodegeneration are early events in DR. Protein tyrosine phosphatase 1B (PTP1B) plays a complex role in monocyte / macrophage activation which may impact DR. We therefore investigated the role of myeloid cell-specific PTP1B using LysMcre-PTP1B fl/fl (LysM-PTP1B) mice, as well as a PTP1B inhibitor, MSI-1436, in the early stages of DR. Mice were rendered diabetic for six weeks using anomer-equilibrated streptozotocin (STZ). Retinal changes were evaluated by histology and immunohistochemistry, and systemic leukocyte activation by flow cytometry. Mitochondrial function in high glucose-challenged, cultured bone marrow-derived macrophages (BMDMs) from LysM-PTP1B and MSI-I436-treated mice was determined in vitro. Both myeloid cell-specific depletion and pharmacological inhibition of PTP1B prevent STZ-induced retinal neurodegeneration, development of acellular retinal capillaries, as well as microglial and systemic leukocyte activation without effect on development of diabetes. In vitro, inhibition of PTP1B prevented high glucose-induced mitochondrial dysfunction in BMDMs. We conclude that inhibition of PTP1B prevents DR by decreasing myeloid cell-driven inflammation and PTP1B represents a therapeutic target for prevention DR. HighlightsO_LIMyeloid cell PTP1B is required to induce retinal neurodegeneration in diabetes C_LIO_LIBoth local (microglia) and systemic (bone-marrow derived) myeloid cells are implicated C_LIO_LIInhibition of myeloid cell PTP1B prevents development of acellular retinal capillaries in diabetic mice C_LIO_LIPTP1B mediates superoxide production, decreases mitochondrial membrane potential and increases macrophages cell death in chronic conditions associated with abnormally high glucose. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=196 SRC="FIGDIR/small/682409v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@d8f71dorg.highwire.dtl.DTLVardef@47c8bforg.highwire.dtl.DTLVardef@cc800dorg.highwire.dtl.DTLVardef@1eade18_HPS_FORMAT_FIGEXP M_FIG C_FIG
Matching journals
The top 10 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- RPE pseudopods maintain photoreceptor outer segment renewal despite subretinal space expansion in Adam9 knockout mice 94%
- An endothelial SOX18-mevalonate pathway axis enables repurposing of statins for infantile hemangioma 92%
- Inhibition of the Eukaryotic Initiation Factor-2-α Kinase PERK Decreases Risk of Autoimmune Diabetes in Mice 92%
Similar papers in this journal
- Sex-specific attenuation of photoreceptor degeneration by reserpine in a rhodopsin P23H rat model of autosomal dominant retinitis pigmentosa 95%
- Overriding defective FPR chemotaxis signaling in diabetic neutrophil stimulates infection control in diabetic wound 95%
- eNOS-induced vascular barrier disruption in retinopathy by c-Src activation and tyrosine phosphorylation of VE-cadherin 94%
Similar papers in this journal
- Fractalkine-induced microglial vasoregulation occurs within the retina and is altered early in diabetic retinopathy 98%
- Corticosteroids prevent pathological angiogenesis yet compromise reparative vascular remodeling in the retina 95%
- RIP1 kinase mediates angiogenesis by modulating macrophages in experimental neovascularization 93%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.