Abstract
The interaction between genetic and environmental factors determines the development of type 1 diabetes (T1D). Some viruses are capable of infecting and damaging pancreatic β-cells, whose antiviral response could be modulated by specific viral RNA receptors and sensors such as melanoma differentiation associated gene 5 (MDA5), encoded by the IFIH1 gene. MDA5 has been shown to be involved in pro-inflammatory and immunoregulatory outcomes, thus determining the response of pancreatic islets to viral infections. Although the function of MDA5 has been previously well explored, a detailed immunohistochemical characterization of MDA5 in pancreatic tissues of nondiabetic and T1D donors is still missing. In the present study, we used multiplex immunofluorescence imaging analysis to characterize MDA5 expression and distribution in pancreatic tissues obtained from 22 organ donors (10 nondiabetic autoantibody-negative, 2 nondiabetic autoantibody-positive, 8 recent-onset, and 2 long-standing T1D). In nondiabetic control donors, MDA5 was expressed both in α- and β-cells. The colocalization rate imaging analysis showed that MDA5 was preferentially expressed in α-cells. In T1D donors, we observed an increased colocalization rate of MDA5-glucagon with respect to MDA5-insulin in comparison to nondiabetic controls; such increase was more pronounced in recent-onset with respect to long-standing T1D donors. Of note, an increased colocalization rate of MDA5-glucagon was found in insulin-deficient-islets (IDIs) with respect to insulin-containing-islets (ICIs). Strikingly, we detected the presence of MDA5-positive/hormone-negative endocrine islet-like clusters in T1D donors, presumably due to dedifferentiation or neogenesis phenomena. These clusters were identified exclusively in donors with recent disease onset and not in autoantibody-positive nondiabetic donors or donors with long-standing T1D. In conclusion, we showed that MDA5 is preferentially expressed in α-cells, and its expression is increased in recent-onset T1D donors. Finally, we observed that MDA5 may also characterize the phenotype of dedifferentiated or newly forming islet cells, thus opening to novel roles for MDA5 in pancreatic endocrine cells.
Highlights
Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease characterized by the progressive destruction of pancreatic b-cells by the immune system, leading to the absolute loss of insulin secretory function
melanoma differentiationassociated gene 5 (MDA5) was exclusively expressed in pancreatic islet endocrine cells, as shown by a near perfect colocalization between chromogranin-A and MDA5 (Supplementary Figure 1A, panels A–L)
No MDA5positive, insulin- and glucagon-negative cells were identified in islets or interspersed in the exocrine tissue, confirming that in nondiabetic human pancreas, MDA5 was expressed in endocrine cells, exclusively in a- or in b-cells
Summary
Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease characterized by the progressive destruction of pancreatic b-cells by the immune system, leading to the absolute loss of insulin secretory function. Molecular mechanisms involved in T1D pathogenesis are still under investigation, disease progression and onset have been widely recognized as the result of the interaction between a predisposing genetic background and environmental factors that may trigger b-cell destruction and immune system activation [1]. It has been recently confirmed that the expression of several markers of interferon (IFN) signature (e.g., MxA, PKR, and HLA-I) in the pancreatic islets of T1D and of islet autoantibody-positive donors is tightly correlated with the presence of enteroviral capsid protein-1 (VP1), showing the existence of an antiviral machinery actively contributing to the islet inflammatory response during viral infections in T1D [13]. The activation of antiviral signaling mechanisms is initiated by specific intracellular sensors of viral nucleic acids and/or components. Among these sensors, melanoma differentiationassociated gene 5 (MDA5) is the most important. MDA5 knockdown in b-cells decreased dsRNA-induced cytokine and chemokine expression, limiting the inflammatory response [16]
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