Myeloid cell protein tyrosine phosphatase 1B (PTP1B) drives retinal neurodegeneration in diabetic mice

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