Macrophages limit inflammatory responses by clearing apoptotic cells. Deficiencies in apoptotic cell phagocytosis have been linked to autoimmunity. In this study, we determined the efficiency with which macrophages from diabetes-prone NOD and diabetes-resistant NOR, Idd5, Balb/c, and C57BL/6 mice phagocytose apoptotic thymocytes and NIT-1 insulinoma cells. Peritoneal and bone marrow-derived macrophages from NOD mice engulfed fewer apoptotic thymocytes than macrophages from Balb/c mice (P < 0.05). Peritoneal macrophages from NOR and Idd5 NOD congenic mice were more proficient at engulfment than their NOD counterparts. Annexin V blockade diminished apoptotic thymocyte clearance and heat-labile serum factors augmented clearance. Binding of apoptotic thymocytes to NOD macrophages was also reduced, suggesting that the deficiency in phagocytosis may be partly attributable to a recognition defect. Peritoneal macrophages from female Balb/c and NOD mice were equally efficient in the engulfment of microspheres, suggesting that the phagocytic deficiency observed in NOD mice was specific for apoptotic cells. In summary, we have demonstrated a deficiency in phagocytic function of macrophages from NOD mice. Normal and diabetes-prone neonatal rodents have a wave of ␤-cell apoptosis coincident with the onset of target organ inflammation. A constitutive defect in the clearance of apoptotic ␤-cells may be contributory to the initiation of autoimmunity. Diabetes

Tumor angiogenesis plays a critical role in the tumor progression. Highly upregulated in liver cancer (HULC) is a long noncoding RNA (lncRNA) that acts as an oncogene in gliomas. We found that HULC, vascular endothelial growth factor (VEGF), and ESM-1 (endothelial cell specific molecule 1) expression and microvessel density were positively correlated with grade dependency in glioma patient tissues, and that HULC silencing suppressed angiogenesis by inhibiting glioma cells proliferation and invasion. This process induced anoikis and blocked the cell cycle at G1/S phase via the PI3K/Akt/mTOR signaling pathway, thus regulating the tumor-related genes involved in the above biological behavior in human glioma U87MG and U251 cells. However, these effects were reversed by ESM-1 overexpression, suggesting a mediating role of ESM-1 in the pro-angiogenesis effect of HULC. Our results define the mechanism of the pro-angiogenesis activity of HULC, which shows potential for application as a therapeutic target in glioma.

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Diabetogenic CD8+ T cells are primed in the pancreatic lymph nodes (PLNs) by dendritic cells (DCs) carrying islet cell Ags. TLR signaling modifies DC function. The goal of this study was to determine the effect of TLR9 signaling on diabetogenic CD8+ T cell activation and the course of type 1 diabetes. We explored the effects of CpG oligonucleotide, TLR9 antagonists, and genetic TLR9 deficiency on the activation of diabetogenic CD8+ T cells. NOD bone marrow-derived DCs pulsed with freeze-thawed insulinoma cells in the presence of TLR9 agonist CpG and CD40 agonist induced diabetogenic CD8+ T cell activation. The addition of TLR9 antagonist oligodeoxynucleotide or chloroquine inhibited bone marrow-derived DCs activation and CD8+ T cell priming in response to CpG. CpG alone or with CD40 agonist induced CTL activity that triggered diabetes development in 8.3-TCR transgenic NOD mice. Oligodeoxynucleotide treatment of 8.3-TCR transgenic NOD mice delayed spontaneous diabetes development. Chloroquine treatment delayed the spontaneous onset of diabetes in NOD mice, coincident with the decreased activation of PLN DCs. TLR9−/− NOD mice had delayed onset of diabetes compared with TLR9−/+ NOD littermates. TLR9−/− NOD mice had lower levels of IFN-α in PLNs and decreased frequencies of plasmacytoid DCs and diabetogenic CD8+ T cells compared with NOD mice. We propose that TLR9 activation contributes to the spontaneous onset of diabetes in NOD mice by increasing IFN-α and promoting diabetogenic CD8 T cell activation.

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