| First Author | Liu Y | Year | 2020 |
| Journal | Biochem Biophys Res Commun | Volume | 525 |
| Issue | 3 | Pages | 620-625 |
| PubMed ID | 32115146 | Mgi Jnum | J:306986 |
| Mgi Id | MGI:6712407 | Doi | 10.1016/j.bbrc.2020.02.142 |
| Citation | Liu Y, et al. (2020) The circadian clock protects against ferroptosis-induced sterile inflammation. Biochem Biophys Res Commun 525(3):620-625 |
| abstractText | 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;Arntl(flox/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. |
