Myeloid Cell Protein Tyrosine Phosphatase 1B Drives Retinal Neurodegeneration in Diabetic Mice

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, whereas microglial activation, neuroinflammation, and retinal neurodegeneration are early events in DR. Protein tyrosine phosphatase 1B (PTP1B) plays a complex role in monocyte and macrophage activation, which may affect DR. We investigated the role of myeloid cell-specific PTP1B using LysMcre-PTP1B fl/fl (LysM-PTP1B) transgenic mice, as well as pharmacological inhibition with a PTP1B inhibitor, MSI-1436, in the early stages of DR. Mice were rendered diabetic for 6 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-concentration-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 prevented STZ-induced retinal neurodegeneration, development of acellular retinal capillaries, as well as microglial and systemic leukocyte activation without altering the development of diabetes. In vitro, inhibition of PTP1B prevented high-glucose-level-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.

Myeloid cell PTP1B is required to induce retinal neurodegeneration in diabetes. Both local (microglia) and systemic (bone marrow-derived) myeloid cells are implicated. Inhibition of myeloid cell PTP1B prevents development of acellular retinal capillaries in diabetic mice. PTP1B mediates superoxide production, decreases mitochondrial membrane potential, and, in female mice, increases macrophage cell death in chronic conditions associated with abnormally high glucose levels. Protective effects of PTP1B deletion on diabetic retinopathy were also observed in mice treated with the small molecular PTP1B inhibitor MSI-1436; both retinal neurodegeneration and local glial cell activation were decreased.