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

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.