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Siglecs as mediators of the pancreatic cellular crosstalk in diabetes

Final Report Summary - SIADIA (Siglecs as mediators of the pancreatic cellular crosstalk in diabetes)

The overarching goal of this project is to find a novel treatment for both obesity associated type 2 Diabetes (T2D) and autoimmune type 1 diabetes mellitus (T1D) by inhibiting the activation of immune cells in the pancreas as well as restoring and preserving survival and function of the insulin producing β-cell.
The major cause of the progression of diabetes is the loss in pancreatic β-cell function and survival. Inflammatory products, which are secreted by islet infiltrating cells of the immune system and also by the insulin producing cells themselves, cause β-cell death and are a major pathway towards β-cell destruction. Such inflammatory products can be detected in the circulation in patients with diabetes. Initiated by previous studies from our group, blocking a single cytokine Interleukin-1β has been proven in vitro, in vivo and in clinical studies to be effective for the treatment of T2D, but failed in first trials in patients with T1D. An ultimate strategy to block excessive inflammatory response, and not only the actions of one single cytokine or immune cell activator, but still maintaining a balanced action of the immune system is missing. Since our strategy targets both, immune cells and β-cells, we provide a tool to inhibit immune cell activation in the pancreas together with β-cell protection.
Sialic acid-binding immunoglobulin-like lectins (siglecs) are cell surface molecules, which are responsible for the functional interactions between cells of the immune system. Most siglecs have special inhibitory motifs (ITIMs), and their signals lead to balancing of immune reactions. They trigger a reduction of pro-inflammatory products and thus turn pro-inflammatory cells into anti-inflammatory, inhibit inflammation in the β-cell and restore β-cell survival.
Key cells in T1D are inflammatory macrophages that are recruited to the pancreas, lead to inflammation and β-cell destruction. Loss of Siglec-7 by diabetic stimulation in macrophages led to their activation and increased inflammation. Importantly, Siglec-7 is also expressed on the β-cell. Diabetogenic conditions led to loss of Siglec-7 expression and enhanced cytokine production and β-cell death, while Siglec-7 overexpression restored β-cell function and prevented macrophage infiltration.
Restoration of Siglec-7 expression or signalling may be a potential therapeutic strategy to preserve β-cell function and mass in the manifestation of diabetes. This strategy would not only rescue the β- cells, but also inhibit systemic inflammation observed in diabetes.