TY - JOUR
T1 - The release and activity of HMGB1 in ferroptosis
AU - Wen, Qirong
AU - Liu, Jiao
AU - Kang, Rui
AU - Zhou, Borong
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. This work was supported by the Natural Science Foundation of Guangdong Province ( 2016A030308011 ), the National Natural Science Foundation of China ( 31671435 , 81830048 , and 81772508 ), the Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (2017) , the American Cancer Society (Research Scholar Grant RSG-16-014-01-CDD ), and Lin He's Academician Workstation of New Medicine and Clinical Translation (2017) .
Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2019/3/5
Y1 - 2019/3/5
N2 - Damage-associated molecular pattern molecules (DAMPs) are endogenous danger signals that alert the innate immune system and shape the inflammation response to cell death. However, the release and activity of DAMPs in ferroptosis, a recently identified form of regulated necrosis characterized by iron overload and lipid peroxidation, still remain poorly understood. Here, we demonstrate that HMGB1 is a DAMP released by ferroptotic cells in an autophagy-dependent manner. Both type I and II ferroptosis activators, including erastin, sorafenib, RSL3, and FIN56, induce HMGB1 release in cancer and noncancer cells. In contrast, genetic ablation (using ATG5−/− or ATG7−/− cells) or pharmacologic inhibition (the administration of bafilomycin A1 or chloroquine) of autophagy was found to block ferroptosis activator-induced HMGB1 release. Mechanically, autophagy-mediated HDAC inhibition promotes HMGB1 acetylation, resulting in HMGB1 release in ferroptosis. Moreover, AGER, but not TLR4, is required for HMGB1-mediated inflammation in macrophages in response to ferroptotic cells. These studies suggest that HMGB1 inhibition might have some potential therapeutic effects in ferroptosis-associated human disease.
AB - Damage-associated molecular pattern molecules (DAMPs) are endogenous danger signals that alert the innate immune system and shape the inflammation response to cell death. However, the release and activity of DAMPs in ferroptosis, a recently identified form of regulated necrosis characterized by iron overload and lipid peroxidation, still remain poorly understood. Here, we demonstrate that HMGB1 is a DAMP released by ferroptotic cells in an autophagy-dependent manner. Both type I and II ferroptosis activators, including erastin, sorafenib, RSL3, and FIN56, induce HMGB1 release in cancer and noncancer cells. In contrast, genetic ablation (using ATG5−/− or ATG7−/− cells) or pharmacologic inhibition (the administration of bafilomycin A1 or chloroquine) of autophagy was found to block ferroptosis activator-induced HMGB1 release. Mechanically, autophagy-mediated HDAC inhibition promotes HMGB1 acetylation, resulting in HMGB1 release in ferroptosis. Moreover, AGER, but not TLR4, is required for HMGB1-mediated inflammation in macrophages in response to ferroptotic cells. These studies suggest that HMGB1 inhibition might have some potential therapeutic effects in ferroptosis-associated human disease.
KW - AGER
KW - Autophagy
KW - DAMP
KW - Ferroptosis
KW - HMGB1
KW - Inflammation
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U2 - 10.1016/j.bbrc.2019.01.090
DO - 10.1016/j.bbrc.2019.01.090
M3 - Article
C2 - 30686534
AN - SCOPUS:85060335296
SN - 0006-291X
VL - 510
SP - 278
EP - 283
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 2
ER -