NLRP1, NLRC4 and IL-1α: Novel molecular targets to improve the outcome of pancreatic islet transplantation

• Applicant: Privatdozent Dr. Emmanuel Ampofo
• Subject Area: General and Visceral Surgery ; Endocrinology, Diabetology, Metabolism
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 520736239

Islet transplantation represents a promising therapeutic approach to improve glycometabolic control in type 1 diabetes mellitus patients and in patients suffering from chronic pancreatitis or following pancreatectomy. However, the insufficient revascularization and, thus, hypoxia-induced inflammatory graft failure is a major issue affecting long-term graft survival. In the last years, significant research efforts have been made to identify novel molecular targets, which improve the outcome of islet transplantation. In particular, anti-inflammatory strategies have been shown to reduce islet loss after transplantation. The nucleotide-binding oligomerization domain (NOD)-like receptor protein (NLRP)3 inflammasome is the best-characterized inflammasome regarding to its pathophysiological roles. It has been reported that pancreatic β-cells also express NLRP3 and we have shown that the inhibition of pancreatic islet NLRP3 improves islet graft revascularization. Recently, members of NLRP family NLRP1 and NLRC4 were identified in pancreatic β-cells. However, the function of these inflammatory proteins in β-cells is still unknown. Interestingly, our preliminary results revealed that hypoxia induces the expression of NLRP1 in β-cells, whereas the expression of NLRC4 was solely upregulated in islet macrophages. Based on these findings, we hypothesize that the loss of NLRP1 and NLRC4 in isolated islets also improves islet transplantation. The NLRP3 inflammasome is a crucial signaling node that controls the maturation of two cytokines interleukin (IL)-18 and IL-1β. The function of the latter one in islet transplantation is well investigated. Several studies already reported that host macrophages infiltrate transplanted islets and release various cytokines including IL-1β, leading to early graft failure. Recently, it has been shown that the exposure of β-cells to IL-1β markedly promotes the gene expression of IL-1α. However, detailed analyses of the role of IL-1α in β-cells under physiological and pathophysiological conditions are still missing. Therefore, we hypothesize that the hypoxia-induced inflammatory response stimulates IL-1α expression in islets in an IL-1β-dependent manner. This, in turn, promotes the loss of islets during the initial posttransplant phase. The aim of this research project is not only to identify NLRP1, NLRC4, and IL-1α as novel targets of pancreatic islet transplantation, but also to analyze the underlying molecular mechanisms that contribute to the improved outcome of pancreatic islet transplantation.

• DFG Programme: Research Grants
• International Connection: Canada
• Co-Investigator: Professor Matthias W. Laschke, Ph.D.
• Cooperation Partner: Professor Dr. Patrick MacDonald