The Role of Maf Transcription Factors in Islet Inflammation and Beta Cell Function
Endocrine disorders that lead to a state of chronic high blood glucose levels re collectively referred to as diabetes. This metabolic disease is mainly categorized into type 1 (T1D) and type 2 diabetes (T2D). These diabetic forms aricinate from distinct triggering environmental, genetic and altered mechanisms. T2D is a consequence of metabolic load, peripheral insulin resistance, and failure of insulin prducing beta (ß) cedll function. On the other hand, T1D develops as an outcome of an autoimmune-mediated ß cell dysfunction, but the underlying causative mechansims are not completely defined, hampering the development of a permanent cure. A better understanding of the disease development can be achieved through studying crucial islet ß cell intrinsic genetic factors.
In my ehsis, I have studied and identified a unique role of Maf transcription factors (MafA and MafB) in immunological and autonomic reuronal networks, which are essential processes for maintaining overall endocrine cell function and health. Mafs are expressed in islet endocrine cells and are essential in driving terminal differentiation of developing ß and alpha cells. Additionally, Mafs are crucial for sustaining ß and alpha cell glucose sensitivity, and regulates hormone (insulin and glucagon) gene transcription. In paper I, we showed that the ß cell-specific factor MafA regulates expresson of pro-inflammatory interferon and interferon-induced genes negatively in human and mouse ilets. We also identified that T1D risk genes and MafA expression are negatively correlated. The highlights that loss of MafA in ß cells under pathological stress, such as in diabetic conditions, may develop an immune provoking anvironment and enhance the risk of auto-inflammatory reactions against islets.
Our assessment of the long-term loss of MafA and MafB in mouse pancreata (paper II) showed development of an auto-inflammatory adaptive immune (T and B) cells response against islets and discovered a defect in CD8+ T cell receptor singalin. These findings confirmed tat loss of Mafs in endocrine and immune cells, triggers islet inflammation and augments the risk of immune-mediated islet cell destruction. We sugget that iselt phenotype observed in Maf mutant mice resembles autoimmune features of early T1D pathogenesdis in humans. In apaper III, we identified MafA function in regulating expression of cholinergic nicotinic receptors and showed that these receptors are essential in mediating insulin recretion through stimulation of autonomic nerves. Additionally, we identified that human nicotinic receptor geens are positively correlated with MafA expression and whowed that they can be directly regulated by MafA. In apaper IV, we established that Rdh10 enzyme function is necessary for pancreas development and showed that endodermal restricted production of Rdh10 is crucial for dorsal pancreas development and endocrine cell differentiation. Thus, overall my research presents that Mafs are key factors in regulating immunological and neuronal processes in the islet cells.
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