ST8Sia6 generated α2,8-disialic acids mitigate hyperglycemia in multiple low dose streptozocin-induced diabetes
| Autor: | Paul Belmonte, Michael Shapiro, Shaylene McCue, Matthew Rajcula, Virginia Smith Shapiro |
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| Rok vydání: | 2019 |
| Předmět: | |
| Zdroj: | The Journal of Immunology. 202:68.16-68.16 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | Type 1 diabetes is an autoimmune disease that destroys insulin-producing beta cells in the pancreatic islets. Although exogenous insulin replacement therapy is lifesaving, precise blood glucose management remains a significant challenge. Experimental islet transplantation restores normoglycemia, but the lack of available islets and graft rejection present major barriers to widespread adoption as standard therapy. The islet resident macrophage (IRM) is in close contact with beta cells, efficiently presents islet antigen to autoreactive T cells, and is critical to disease occurrence. We have demonstrated that murine IRMs express high levels of Siglec-E, an immune-regulatory receptor that preferentially binds α2,8-disialic acids in cis or in trans. When islets were exposed to streptozocin (STZ)-induced stress in culture, beta cells upregulated ligands for Siglec-E. To determine the biological significance of this, we generated a mouse model where ST8Sia6, the sialyltransferase that produces α2,8-disialic acids and thus Siglec-E ligands, is constitutively overexpressed in beta cells. This increased trans Siglec-E binding affinity to the beta cell surface, and mitigated hyperglycemia in the multiple low-dose STZ model of diabetes. Significant reduction in blood sugar was evident at 14 days post-initial injection of STZ, coinciding with T cell infiltration of islets. T cells from ST8Sia6+ islets were less activated when compared to littermates. This work reveals a novel and important role for Siglec-E in autoimmune diabetes and provides insight into how rational targeting of this immune receptor may instruct islet-residing antigen presenting cells to provide local tolerance signals in the setting of islet transplantation. |
| Databáze: | OpenAIRE |
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