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26-02-2024 | Type 1 Diabetes | Extended Article

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

Authors: Alexandra Coomans de Brachène, Maria Ines Alvelos, Florian Szymczak, Priscila L. Zimath, Angela Castela, Bianca Marmontel de Souza, Arturo Roca Rivada, Sandra Marín-Cañas, Xiaoyan Yi, Anne Op de Beeck, Noel G. Morgan, Sebastian Sonntag, Sayro Jawurek, Alexandra C. Title, Burcak Yesildag, François Pattou, Julie Kerr-Conte, Eduard Montanya, Montserrat Nacher, Lorella Marselli, Piero Marchetti, Sarah J. Richardson, Decio L. Eizirik

Published in: Diabetologia | Issue 5/2024

Abstract

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.

Graphical Abstract

Available only for authorised users

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Title: Interferons are key cytokines acting on pancreatic islets in type 1 diabetes
Authors: Alexandra Coomans de Brachène
Maria Ines Alvelos
Florian Szymczak
Priscila L. Zimath
Angela Castela
Bianca Marmontel de Souza
Arturo Roca Rivada
Sandra Marín-Cañas
Xiaoyan Yi
Anne Op de Beeck
Noel G. Morgan
Sebastian Sonntag
Sayro Jawurek
Alexandra C. Title
Burcak Yesildag
François Pattou
Julie Kerr-Conte
Eduard Montanya
Montserrat Nacher
Lorella Marselli
Piero Marchetti
Sarah J. Richardson
Decio L. Eizirik
Publication date: 26-02-2024
Publisher: Springer Berlin Heidelberg
Keywords: Type 1 Diabetes
Cytokines
Published in: Diabetologia / Issue 5/2024
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-024-06106-7

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