Interferon-γ induces salivary gland epithelial cell ferroptosis in Sjogren's syndrome via JAK/STAT1-mediated inhibition of system Xc

Free Radic Biol Med. 2023 Aug 20:205:116-128. doi: 10.1016/j.freeradbiomed.2023.05.027. Epub 2023 Jun 5.

Abstract

The elevated level of interferon-γ (IFN-γ) in Sjogren's syndrome (SS) triggers salivary gland epithelial cells (SGEC) death. However, the underlying mechanisms of IFN-γ-induced SGEC death modes are still not fully elucidated. We found that IFN-γ triggers SGEC ferroptosis via Janus kinase/signal transducer and activator of transcription 1 (JAK/STAT1)-mediated inhibition of cystine-glutamate exchanger (System Xc-). Transcriptome analysis revealed that ferroptosis-related markers are differentially expressed in SS human and mouse salivary glands with distinct upregulation of IFN-γ and downregulation of glutathione peroxidase 4 (GPX4) and aquaporin 5 (AQP5). Inducing ferroptosis or IFN-γ treatment in the Institute of cancer research (ICR) mice aggravated and inhibition of ferroptosis or IFN-γ signaling in SS model non-obese diabetic (NOD) mice alleviated ferroptosis in the salivary gland and SS symptoms. IFN-γ activated STAT1 phosphorylation and downregulated system Xc- components solute carrier family 3 member 2 (SLC3A2), glutathione, and GPX4 thereby triggering ferroptosis in SGEC. JAK or STAT1 inhibition in SGEC rescued IFN-γ-downregulated SLC3A2 and GPX4 as well as IFN-γ-induced cell death. Our results indicate the role of ferroptosis in SS-related death of SGEC and SS pathogenicity.

Keywords: Cystine-glutamate exchanger; Ferroptosis; Interferon-γ; Janus kinase/signal transducer and activator of transcription 1 signaling; Salivary gland epithelial cells; Sjogren's syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Epithelial Cells / metabolism
  • Ferroptosis* / genetics
  • Humans
  • Interferon-gamma / metabolism
  • Janus Kinases / metabolism
  • Mice
  • Mice, Inbred NOD
  • STAT1 Transcription Factor / genetics
  • STAT1 Transcription Factor / metabolism
  • Salivary Glands / metabolism
  • Sjogren's Syndrome* / genetics
  • Sjogren's Syndrome* / metabolism

Substances

  • Interferon-gamma
  • STAT1 protein, human
  • STAT1 Transcription Factor
  • Janus Kinases