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The dysregulation of receptor tyrosine kinases (RTKs) in multiple cell types during chronic inflammation is indicative of their pathogenic role in autoimmune diseases. Among the many RTKs, vascular endothelial growth factor receptor (VEGFR) stands out for its multiple effects on immunity, vascularization, and cell migration. Herein, we examined whether VEGFR participated the pathogenesis of type 1 diabetes (TID) in nonobese diabetic (NOD) mice. We found that RTK inhibitors (RTKIs) and VEGF VEGFR-2 antibodies reversed diabetes when administered at the onset of hyperglycemia. Increased VEGF expression promoted islet vascular remodeling in NOD mice, and inhibition of VEGF activity with RTKIs abrogated the increase in islet vascularity, impairing T-cell migration into the islet and improving glucose control. Metabolic studies confirmed that RTKIs worked by preserving islet function, as treated mice had improved glucose tolerance without affecting insulin sensitivity. Finally, examination of human pancreata from patients with TID revealed that VEGFR-2 was confined to the islet vascularity, which was increased in inflamed islets. Collectively, this work reveal a previously unappreciated role for VEGFR-2 signaling in the pathogenesis of TID by controlling T-cell accessibility to the pancreatic islets and highlights a novel application of VEGFR-2 antagonists for the therapeutic treatment of T1D. [ABSTRACT FROM AUTHOR]

Cell proliferation and cell death must be closely regulated to maintain the integrity of the immune system during the lifetime of multicellular organisms. Proliferative expansion of lymphoid cells is required for effective immune responses against invading microorganisms. However, following infection eradication, expanded effector cells must be eliminated to prevent non-adaptive accumulation of cells. Therefore, higher vertebrates have developed an extensive network of signal transduction pathways that allow integration of cell survival and cell death stimuli. This network functions to ensure the controlled activation and expansion of cells during an immune response and the deletion of lymphoid cells that are no longer needed at the end of an immune response. Extracellular signals appear to control both mechanisms. Ultimate responses are integrated through cell surface receptors that are linked to intracellular signaling cascades. These signal transduction pathways converge to regulate cell fate at both transcriptional and post-transcriptional levels. In this review, the role of pathways triggered by TNFR-related molecules that determine the fate of lymphoid cells during development and activation is summarized. [ABSTRACT FROM AUTHOR]