MicroRNAs: Novel Players in the Dialogue between Pancreatic Islets and Immune System in Autoimmune Diabetes

Abstract

MicroRNAs are small noncoding RNA molecules that regulate gene expression in all cell types. Therefore, these tiny noncoding RNA molecules are involved in a wide range of biological processes, exerting functional effects at cellular, tissue, and organ level. In pancreatic islets of Langerhans, including beta-cells, microRNAs are involved in cell differentiation as well as in insulin secretion, while in immune cells they have been shown to play pivotal roles in development, activation, and response to antigens. Indeed, it is not surprising that microRNA alterations can lead to the development of several diseases, including type 1 diabetes (T1D). Type 1 diabetes is the result of a selective autoimmune destruction of insulin-producing beta-cells, characterized by islet inflammation (insulitis), which leads to chronic hyperglycemia. Given the growing importance of microRNA in the pathophysiology of T1D, the aim of this review is to summarize the most recent data on the potential involvement of microRNAs in autoimmune diabetes. Specifically, we will focus on three different aspects: (i) microRNAs as regulators of immune homeostasis in autoimmune diabetes; (ii) microRNA expression in pancreatic islet inflammation; (iii) microRNAs as players in the dialogue between the immune system and pancreatic endocrine cells.

Figure 1

MicroRNAs as major players in immune-mediated beta-cell damage in autoimmune diabetes. The figure reports a representing scheme of microRNAs (miRNA) response induced by infiltrating immune cells (mainly CD4+ and CD8+ T-lymphocytes, B-lymphocytes, and macrophages) and secreted cytokines. The secretion of IL-1β, TNF-α, and IFN-γ induces changes in expression of several miRNAs. Specifically, upregulation of miR-146a, miR-34, miR-21, and miR-29s is shown. Each miRNA targeting specific genes (with consequent inhibition of their expression) is reported as a red dotted arrow, while the activation of a specific mechanism is represented as green dotted arrow. Upregulation of miR-146a induces the activation of apoptosis pathway through a not yet understood mechanism, while inhibiting the expression of Traf6 and Irak1 (NF-κB pathway). Upregulation of miR-34 leads to reduction of antiapoptotic gene Bcl-2 and of VAMP2, a molecule involved in the fusion of insulin granules to the plasma membrane. The increased expression of miR-21 leads to a partial protection from apoptosis through the inhibition of cell death inducer PDCD4. It also decreases expression levels of VAMP2, thus blocking insulin secretion. Finally, upregulation of miR-29s (miR-29a-b-c) leads to reduction of OC2 (Onecut2), a transcriptional repressor of granuphilin-4 (inhibitor of insulin secretion), thus leading to its upregulation and subsequently to a reduced insulin exocytosis.