Type 1 diabetes (T1D) is a chronic multifactorial autoimmune disease that includes 5-10% of diabetes cases and is characterized by the immune-mediated insulin secreting β cell destruction with consequent loss of β cell mass and hyperglycemia. In autoimmune diabetes, the selective β cell destruction is the result of a series of mechanisms including, but not limiting to autoreactive T cells direct β cell destruction and inflammatory stress, resulting in a dramatic loss of functional β cell mass. MicroRNAs are small non coding 19-24 nucleotides RNAs that negatively regulate gene expression, binding selectively their mRNAs target and leading to their translational repression and/or degradation. It was also remarked that miRNAs are involved in T1D pathogenesis, by regulating a series of processes both in β cells and lymphocytes that ranged from cell metabolic dysfunction and apoptosis to dedifferentiation and immune molecule secretion. Additionally, it has been suggested that secreted microRNAs can take part in the communication between immune system and pancreatic endocrine cells; therefore, studying such dialogue could help to better understand T1D pathogenesis and to the identification of biomarkers that reflect the diseased status of the target organ. In order to investigate the role of miRNAs as biomarkers of T1D pathogenesis both at endocrine and immune interface, the study can be subdivided into the following sections: 1) MiRNAs as circulating biomarkers of diseased-target tissue- In this section, miR-409-3p was found downregulated in murine and human plasma of T1D subjects, highlight the importance to find a lymphocyte deriving circulating biomarker that reflect the target organ pathological status. 2) MiRNAs as modulators of β cell function- miR-183-5p was downregulated in pancreatic endocrine tissue of mouse and human diabetic patients, contributing to β cell protection from apoptosis through the modulation of anti-apoptotic factor Bach2 and through the potential induction of a dedifferentiation phenomenon. This study demonstrated that β cells are able to react to stress and to cell damage through a miRNA-mediated protective phenomenon. 3) Secreted/Immune-derived miRNAs as mediators of β cell apoptosis- Exosomes enriched in miR-142-3p/5p and miR-155 and secreted by T autoreactive lymphocytes, induced selective β cell apoptosis, through the modulation of proinflammatory chemokine expression. The selective AAV “Sponge” inactivation of miR-142-3p/5p, miR-150 and miR-155 induced β cell protection of prediabetic NOD mice from the autoimmune attack that occurs in T1D, inducing the reduction of the proinflammatory chemokine CXCL10 specifically in β cells than in α cells. Such study remarked the exosome-mediated communication dynamics between immune system components and endocrine cells in the center of this dialogue, miRNAs give their fundamental contribution and more importantly, as it has already been reported, it’s possible to actively and therapeutically interfere in this dialogue in order to positively change the β cell fate.
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|Titolo:||MicroRNAs role in type 1 diabetes pathogenesis: a dialogue between pancreatic islets and immune system|
|Citazione:||Mancarella, F. (2019). MicroRNAs role in type 1 diabetes pathogenesis: a dialogue between pancreatic islets and immune system.|
|Appare nelle tipologie:||8.1 Tesi Dottorato|