Abstract
BackgroundType 1 diabetes (T1D) is an autoimmune disease characterized by the progressive destruction of pancreatic beta cells. Interferon-α (IFNα), an antiviral cytokine, is expressed in the pancreatic islets in early T1D, which may be secondary to viral infections. However, not all patients harboring a type I IFN signature present signals of viral infection, suggesting that this response might be initiated by other “danger signals”. Accumulation of mitochondrial double-stranded RNA (mtdsRNA; a danger signal), secondary to silencing of members of the mitochondrial degradosome, PNPT1 and SUV3, has been described to activate the innate immune response.MethodsTo evaluate whether mtdsRNA represents a “danger signal” for pancreatic beta cells in the context of T1D, we silenced PNPT1 and/or SUV3 in slowly proliferating human insulin-secreting EndoC-βH1 cells and in non-proliferating primary human beta cells and evaluated dsRNA accumulation by immunofluorescence and the type I IFN response by western blotting and RT-qPCR.ResultsOnly the simultaneous silencing of PNPT1/SUV3 induced dsRNA accumulation in EndoC-βH1 cells but not in dispersed human islets, and there was no induction of a type I IFN response. By contrast, silencing of these two genes individually was enough to induce dsRNA accumulation in fibroblasts present in the human islet preparations.ConclusionsThese data suggest that accumulation of endogenous mtdsRNA following degradosome knockdown depends on the proliferative capacity of the cells and is not a mediator of the type I IFN response in human pancreatic beta cells.
Highlights
Type 1 diabetes (T1D) is an autoimmune disease characterized by the progressive destruction of pancreatic beta cells
We presently evaluated whether generation of mitochondrial double-stranded RNA (mtdsRNA) is part of the potential endogenous “danger signals” generated in pancreatic beta cells that may contribute to trigger a local innate immune response in the context of T1D
PNPT1 silencing, alone or together with Adenosine deaminase RNA-specific (ADAR) silencing, does not induce double-stranded RNA (dsRNA) accumulation or a type I IFN response in EndoC‐βH1 cells To study the possible role of PNPT1 and mtdsRNA in the initiation of the innate immune response in pancreatic beta cells, as previously described in HeLa cells [15], we used two different Small-interfering RNA (siRNA)
Summary
Type 1 diabetes (T1D) is an autoimmune disease characterized by the progressive destruction of pancreatic beta cells. Not all patients harboring a type I IFN signature present signals of viral infection, suggesting that this response might be initiated by other “danger signals”. Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by the progressive destruction of pancreatic beta cells by the immune system and subsequent loss of insulin secretion. Enterovirus RNA or proteins are found in blood, stool or pancreatic islets from T1D patients more frequently than in controls [7, 8], but many patients that develop disease don’t show a clear correlation with viral infection [9], suggesting the existence of other “danger signals” that may initiate a type I IFN response in the context of T1D
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
