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Critical roles of tumor necrosis factor-related apoptosis-inducing ligand in type 1 diabetes
Salah-Eddine Lamhamedi-Cherradi1, Shijun Zheng, Roland M Tisch
1Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Abstract:
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis of tumor cells but not most normal cells. Its roles in normal nontransformed tissues are not clear. To explore the potential roles of TRAIL in type 1 diabetes, we examined the consequences of TRAIL blockade or TRAIL deficiency in two animal models of autoimmune diabetes. In the first model, NOD mice received an injection of a soluble TRAIL receptor to block TRAIL function. This significantly accelerated the diabetes and increased the degree of autoimmune inflammation in both pancreatic islets and salivary glands. The GAD65-specific immune responses were also significantly enhanced in animals that received the soluble TRAIL receptor. In the second model, we treated normal and TRAIL-deficient C57BL/6 mice with multiple low-dose streptozotocin to induce diabetes. We found that both the incidence and the degree of islet inflammation were significantly enhanced in TRAIL-deficient animals. On the basis of these observations, we conclude that TRAIL deficiency accelerates autoimmune diabetes and enhances autoimmune responses.
Insights
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) normally protects against autoimmune diabetes. TRAIL deficiency or blockade accelerates type 1 diabetes development and enhances autoimmune responses in pancreatic islets.
Area of Science:
- Immunology
- Endocrinology
- Cell Biology
Background:
- Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is known for inducing apoptosis in tumor cells.
- The function of TRAIL in normal, nontransformed tissues, particularly in the context of autoimmune diseases like type 1 diabetes, is not well understood.
Purpose of the Study:
- To investigate the role of TRAIL in the pathogenesis of type 1 diabetes.
- To determine the effects of TRAIL blockade or deficiency on autoimmune diabetes development and associated immune responses.
Main Methods:
- Utilized two distinct animal models for autoimmune diabetes: NOD mice treated with a soluble TRAIL receptor and TRAIL-deficient C57BL/6 mice treated with streptozotocin.
- Assessed the incidence and severity of diabetes, pancreatic islet inflammation, salivary gland inflammation, and GAD65-specific immune responses.
Main Results:
- Blocking TRAIL function in NOD mice significantly accelerated diabetes and intensified autoimmune inflammation in pancreatic islets and salivary glands.
- TRAIL-deficient mice exhibited increased incidence and severity of islet inflammation when induced to develop diabetes.
- GAD65-specific immune responses were enhanced in animals with blocked TRAIL function.
Conclusions:
- TRAIL plays a protective role in preventing the development of autoimmune diabetes.
- TRAIL deficiency or blockade exacerbates autoimmune diabetes by enhancing inflammatory responses in pancreatic islets and promoting autoimmune reactions.
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