The circadian clock protects against ferroptosis-induced sterile inflammation

Yang Liu, Yuan Wang, Jiao Liu, Rui Kang, Daolin Tang

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

The circadian clock, a biochemical oscillator, plays a fundamental role in health and diseases. Ferroptosis, a type of regulated cell death driven by oxidative stress, is a prominent feature in iron-induced tissue injury. However, whether an impaired circadian clock contributes to ferroptosis-induced sterile inflammation remains unknown. Here, we show that the circadian transcription factor ARNTL (also known as BMAL1) protects against experimental acute pancreatitis through blocking the ferroptosis-mediated release of HMGB1, a mediator of sterile inflammation. We utilized a Cre/LoxP system to generate mice with a specific depletion of Arntl in the pancreas (Pdx1-Cre;Arntlflox/flox). These Arntl-deficient mice developed L-arginine–induced acute pancreatitis more rapidly than controls, with increased mortality, tissue injury, neutrophil infiltration, and HMGB1 release. In contrast, the administration of liproxstatin-1 (a ferroptosis inhibitor) or anti-HMGB1 neutralizing antibody attenuated the development of acute pancreatitis in the Arntl-deficient mice. Mechanistically, pancreatic ARNTL is a key regulator of the expression of multiple antioxidant or membrane repair systems (e.g., SLC7A11, GPX4, SOD1, TXN, NFE2L2, and CHMP5) to suppress ferroptotic tissue injury. Collectively, these findings uncover a novel link between the circadian clock and ferroptotic response in inflammation and pancreatic injury.

Original languageEnglish (US)
Pages (from-to)620-625
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume525
Issue number3
DOIs
StatePublished - May 7 2020

Keywords

  • Circadian clock
  • DAMP
  • Ferroptosis
  • Inflammation
  • Pancreatitis

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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