TY - JOUR
T1 - The circadian clock protects against ferroptosis-induced sterile inflammation
AU - Liu, Yang
AU - Wang, Yuan
AU - Liu, Jiao
AU - Kang, Rui
AU - Tang, Daolin
N1 - Funding Information:
We thank Dave Primm (Department of Surgery, University of Texas Southwestern Medical Center ) for his critical reading of the manuscript. D.T. was supported by the American Cancer Society (Research Scholar Grant RSG-16-014-01-CDD ). J.L. is supported by grants from the National Natural Science Foundation of China ( 31671435 , 81400132 , and 81772508 ).
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/5/7
Y1 - 2020/5/7
N2 - 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.
AB - 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.
KW - Circadian clock
KW - DAMP
KW - Ferroptosis
KW - Inflammation
KW - Pancreatitis
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U2 - 10.1016/j.bbrc.2020.02.142
DO - 10.1016/j.bbrc.2020.02.142
M3 - Article
C2 - 32115146
AN - SCOPUS:85080091257
SN - 0006-291X
VL - 525
SP - 620
EP - 625
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 3
ER -