Interferons are key cytokines acting on pancreatic islets in type 1 diabetes.

Autor: Coomans de Brachène A; ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium. alexandra.coomans.de.brachene@ulb.be., Alvelos MI; ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium., Szymczak F; ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium., Zimath PL; ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium., Castela A; ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium., Marmontel de Souza B; ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium., Roca Rivada A; ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium., Marín-Cañas S; ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium., Yi X; ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium., Op de Beeck A; ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium., Morgan NG; Islet Biology Exeter (IBEx), Exeter Centre of Excellence for Diabetes Research (EXCEED), Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Exeter, UK., Sonntag S; InSphero AG, Schlieren, Switzerland.; University of Applied Sciences and Arts Northwestern Switzerland, Basel, Switzerland., Jawurek S; InSphero AG, Schlieren, Switzerland., Title AC; InSphero AG, Schlieren, Switzerland., Yesildag B; InSphero AG, Schlieren, Switzerland., Pattou F; European Genomic Institute for Diabetes, UMR 1190 Translational Research for Diabetes, Inserm, CHU Lille, University of Lille, Lille, France., Kerr-Conte J; European Genomic Institute for Diabetes, UMR 1190 Translational Research for Diabetes, Inserm, CHU Lille, University of Lille, Lille, France., Montanya E; Hospital Universitari Bellvitge, Bellvitge Biomedical Research Institute (IDIBELL), Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) and University of Barcelona, Barcelona, Spain., Nacher M; Hospital Universitari Bellvitge, Bellvitge Biomedical Research Institute (IDIBELL), Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) and University of Barcelona, Barcelona, Spain., Marselli L; Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy., Marchetti P; Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy., Richardson SJ; Islet Biology Exeter (IBEx), Exeter Centre of Excellence for Diabetes Research (EXCEED), Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Exeter, UK., Eizirik DL; ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium. decio.laks.eizirik@ulb.be.
Jazyk: angličtina
Zdroj: Diabetologia [Diabetologia] 2024 May; Vol. 67 (5), pp. 908-927. Date of Electronic Publication: 2024 Feb 26.
DOI: 10.1007/s00125-024-06106-7
Abstrakt: Aims/hypothesis: The proinflammatory cytokines IFN-α, IFN-γ, IL-1β and TNF-α may contribute to innate and adaptive immune responses during insulitis in type 1 diabetes and therefore represent attractive therapeutic targets to protect beta cells. However, the specific role of each of these cytokines individually on pancreatic beta cells remains unknown.
Methods: We used deep RNA-seq analysis, followed by extensive confirmation experiments based on reverse transcription-quantitative PCR (RT-qPCR), western blot, histology and use of siRNAs, to characterise the response of human pancreatic beta cells to each cytokine individually and compared the signatures obtained with those present in islets of individuals affected by type 1 diabetes.
Results: IFN-α and IFN-γ had a greater impact on the beta cell transcriptome when compared with IL-1β and TNF-α. The IFN-induced gene signatures have a strong correlation with those observed in beta cells from individuals with type 1 diabetes, and the level of expression of specific IFN-stimulated genes is positively correlated with proteins present in islets of these individuals, regulating beta cell responses to 'danger signals' such as viral infections. Zinc finger NFX1-type containing 1 (ZNFX1), a double-stranded RNA sensor, was identified as highly induced by IFNs and shown to play a key role in the antiviral response in beta cells.
Conclusions/interpretation: These data suggest that IFN-α and IFN-γ are key cytokines at the islet level in human type 1 diabetes, contributing to the triggering and amplification of autoimmunity.
(© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
Databáze: MEDLINE
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