DEXI, a candidate gene for type 1 diabetes, modulates rat and human pancreatic beta cell inflammation via regulation of the type I IFN/STAT signalling pathway

• Published in: Diabetologia 2019-03, Vol.62 (3), p.459-472
• Main Authors: Dos Santos, Reinaldo S., Marroqui, Laura, Velayos, Teresa, Olazagoitia-Garmendia, Ane, Jauregi-Miguel, Amaia, Castellanos-Rubio, Ainara, Eizirik, Decio L., Castaño, Luis, Santin, Izortze
• Format: Article
• Language: English
• Subjects: Animals; Antiviral drugs; Apoptosis; Apoptosis - genetics; Beta cells; Chemokines; Chromatin; Chromosome 16; Dexamethasone; Diabetes; Diabetes mellitus; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - metabolism; Diabetes Mellitus, Type 1 - pathology; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Double-stranded RNA; Environmental factors; Gene expression; Gene regulation; Human Physiology; Humans; Immune response; Inflammation; Inflammation - genetics; Inflammation - metabolism; Inflammation - pathology; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; Interferon; Interferon Type I - metabolism; Internal Medicine; Medicine; Medicine & Public Health; Membrane Proteins - genetics; Membrane Proteins - metabolism; Metabolic Diseases; Pancreas; Polymorphism, Single Nucleotide; Rats; RNA, Double-Stranded; Rodents; Signal transduction; Signal Transduction - genetics; Single-nucleotide polymorphism; STAT Transcription Factors - metabolism; Stat1 protein; Transcription; Western blotting
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-018-4782-0

Aims/hypothesis The initial stages of type 1 diabetes are characterised by an aberrant islet inflammation that is in part regulated by the interaction between type 1 diabetes susceptibility genes and environmental factors. Chromosome 16p13 is associated with type 1 diabetes and CLEC16A is thought to be the aetiological gene in the region. Recent gene expression analysis has, however, indicated that SNPs in CLEC16A modulate the expression of a neighbouring gene with unknown function named DEXI , encoding dexamethasone-induced protein (DEXI). We therefore evaluated the role of DEXI in beta cell responses to ‘danger signals’ and determined the mechanisms involved. Methods Functional studies based on silencing or overexpression of DEXI were performed in rat and human pancreatic beta cells. Beta cell inflammation and apoptosis, driven by a synthetic viral double-stranded RNA, were evaluated by real-time PCR, western blotting and luciferase assays. Results DEXI-silenced beta cells exposed to a synthetic double-stranded RNA (polyinosinic:polycytidylic acid [PIC], a by-product of viral replication) showed reduced activation of signal transducer and activator of transcription (STAT) 1 and lower production of proinflammatory chemokines that was preceded by a reduction in IFNβ levels. Exposure to PIC increased chromatin-bound DEXI and IFNβ promoter activity. This effect on IFNβ promoter was inhibited in DEXI-silenced beta cells, suggesting that DEXI is implicated in the regulation of IFNβ transcription. In a mirror image of knockdown experiments, DEXI overexpression led to increased levels of STAT1 and proinflammatory chemokines. Conclusions/interpretation These observations support DEXI as the aetiological gene in the type 1 diabetes-associated 16p13 genomic region, and provide the first indication of a link between this candidate gene and the regulation of local antiviral immune responses in beta cells. Moreover, our results provide initial information on the function of DEXI.