Heatstroke induces liver injury via IL-1β and HMGB1-induced pyroptosis.
OBJECTIVE
Liver injury is a common complication of heat stroke (HS), and often constitutes a direct cause for patient death. The cellular and molecular mechanism underlying HS-induced liver injury remains unclear. Recent evidence indicates that inflammasome plays an important role in mediating sterile inflammation triggered by tissue damage. Using a rat HS model, we identified a novel mechanism by which inflammasome-dependent interleukin-1β (IL-1β) activation and hepatocyte pyroptosis mediate HS-induced liver injury.


METHODS
To induce HS, rats were subjected to heat exposure. Inhibition of inflammasomes was achieved by RNA silencing and pharmacologic inhibitor prior to heat exposure. Inflammasome assembly, caspase-1 activation, histological changes, as well as serum levels of liver enzymes were measured.


RESULTS
We demonstrated that the onset of HS activated inflammasome in the liver as evidenced by increased capase-1 activity and the association of inflammasome components NOD-like receptor family pyrin domain containing 3 (Nlrp3) and apoptosis speck-like protein containing a caspase-recruitment domain (ASC); and the activated inflammasome, in turn, induced IL-1β activation and hepatocyte pyroptosis, and subsequent augmented liver injury. HS-induced hepatocyte inflammasome activation seems to be high-mobility group box 1 (HMGB1) dependent. Inhibition of Nlrp3, caspase-1, or HMGB1 prevented HS-induced liver inflammation and ameliorated liver injury.


CONCLUSIONS
These findings demonstrate an important role of HMGB1 in mediating inflammasome activation in the development of liver injury following HS, and suggest that targeting inflammasome may represent a novel therapeutic strategy to limit cell death and prevent liver failure after HS.
Department of Gastroenterology, 303 Hospital of People's Liberation Army, Nanning 530021, PR China; Department of Intensive Care Unit, General Hospital of Guangzhou Military Command, Guangzhou 510010, PR China. Electronic address: gytools@sina.com.
Yan
Y
Geng
State Key Laboratory of Organ Failure Research, Institute of Antibody Engineering, Southern Medical University, Guangzhou 510515, PR China. Electronic address: mqqqm2006@163.com.
Qiang
Q
Ma
Department of Graduate School, Southern Medical University, Guangzhou 510515, PR China.
Ya-Nan
YN
Liu
Department of Graduate School, Southern Medical University, Guangzhou 510515, PR China; Department of Intensive Care Unit, General Hospital of Guangzhou Military Command, Guangzhou 510010, PR China.
Na
N
Peng
Department of Graduate School, Southern Medical University, Guangzhou 510515, PR China; Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Fang-Fang
FF
Yuan
Department of Neurology, The Fifth People's Hospital of Chongqing, Chongqing 400062, PR China; Department of Intensive Care Unit, General Hospital of Guangzhou Military Command, Guangzhou 510010, PR China.
Xing-Gui
XG
Li
State Key Laboratory of Organ Failure Research, Institute of Antibody Engineering, Southern Medical University, Guangzhou 510515, PR China.
Ming
M
Li
State Key Laboratory of Organ Failure Research, Institute of Antibody Engineering, Southern Medical University, Guangzhou 510515, PR China.
Ying-Song
YS
Wu
Department of Intensive Care Unit, General Hospital of Guangzhou Military Command, Guangzhou 510010, PR China.
Bing-ling
BL
Li
Department of Intensive Care Unit, General Hospital of Guangzhou Military Command, Guangzhou 510010, PR China.
Wei-bing
WB
Song
Department of Toxicology, Guangzhou Center for Disease Control and Prevention, Guangzhou 510515, PR China.
Wei
W
Zhu
State Key Laboratory of Organ Failure Research, Institute of Antibody Engineering, Southern Medical University, Guangzhou 510515, PR China.
Wei-Wen
WW
Xu
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. Electronic address: jif7@pitt.edu.
Jie
J
Fan
Department of Intensive Care Unit, General Hospital of Guangzhou Military Command, Guangzhou 510010, PR China. Electronic address: drggyn@163.com.
Lei
L
Su
D000818:Animals; D002352:Carrier Proteins / Q000502:physiology; D020170:Caspase 1 / Q000378:metabolism; D024243:HMGB1 Protein / Q000502:physiology*; D018883:Heat Stroke / Q000150:complications*; D022781:Hepatocytes / Q000473:pathology; D053583:Interleukin-1beta / Q000502:physiology*; D008107:Liver Diseases / Q000209:etiology*; D008297:Male; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D000069292:Pyroptosis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013599:Systole
D002352:Carrier Proteins; D024243:HMGB1 Protein; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C573346:Nlrp3 protein, rat; D020170:Caspase 1
Caspase-1; Hyperthermia; Inflammasome; Nlrp3