ScholarLink (思领科)
错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 发表日期：

    2024年2月26日

查看全文
  • 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

摘要

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