The Role of Maf Transcription Factors in Islet Inflammation and Βeta Cell Function

Endocrine disorders that lead to a state of chronic high blood glucose levels are collectively referred to as diabetes. This metabolic disease is mainly categorized into type 1 (T1D) and type 2 diabetes (T2D). These diabetic forms originate from distinct triggering environmental, genetic, and altered mechanisms. T2D is a consequence of metabolic load, peripheral insulin resistance, and failure of insulin producing beta (β) cell function. On the other hand, T1D develops as an outcome of an autoimmune-mediated β cell destruction, which results in insulin deficiency. Etiology of diabetes is strongly linked with genetic alterations that cause β cell dysfunction, but the underlying causative mechanisms 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 β cell intrinsic genetic factors.In my thesis, I have studied and identified a unique role of Maf transcription factors (MafA and MafB) in immunological and autonomic neuronal 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 β and alpha (α) cells. Additionally, Mafs are crucial for sustaining β and α cell glucose sensitivity, and regulates hormone (insulin and glucagon) gene transcription. In paper I, we showed that the β cell-specific factor MafA regulates expression of pro-inflammatory interferon and interferon-induced genes negatively in human and mouse islets. We also identified that T1D risk genes and MafA expression are negatively correlated. This highlights that loss of MafA in β cells under pathological stress, such as in diabetic conditions, may develop an immune provoking environment 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 signaling. These findings confirmed that loss of Mafs in endocrine and immune cells, triggers islet inflammation and augments the risk of immune-mediated islet cell destruction. We suggest that islet phenotype observed in Maf mutant mice resembles autoimmune features of early T1D pathogenesis in humans. In paper III, we identified MafA function in regulating expression of cholinergic nicotinic receptors and showed that these receptors are essential in mediating insulin secretion through stimulation of autonomic nerves. Additionally, we identified that human nicotinic receptor genes are positively correlated with MAFA expression and showed that they can be directly regulated by MafA. In paper 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