Necroptosis is a key mediator of enterocytes loss in intestinal ischaemia/reperfusion injury.
Cell death is an important biological process that is believed to have a central role in intestinal ischaemia/reperfusion (I/R) injury. While the apoptosis inhibition is pivotal in preventing intestinal I/R, how necrotic cell death is regulated remains unknown. Necroptosis represents a newly discovered form of programmed cell death that combines the features of both apoptosis and necrosis, and it has been implicated in the development of a range of inflammatory diseases. Here, we show that receptor-interacting protein 1/3 (RIP1/3) kinase and mixed lineage kinase domain-like protein recruitment mediates necroptosis in a rat model of ischaemic intestinal injury in vivo. Furthermore, necroptosis was specifically blocked by the RIP1 kinase inhibitor necrostatin-1. In addition, the combined treatment of necrostatin-1 and the pan-caspase inhibitor Z-VAD acted synergistically to protect against intestinal I/R injury, and these two pathways can be converted to one another when one is inhibited. In vitro, necrostatin-1 pre-treatment reduced the necroptotic death of oxygen-glucose deprivation challenged intestinal epithelial cell-6 cells, which in turn dampened the production of pro-inflammatory cytokines (tumour necrosis factor-α and interleukin-1β), and suppressed high-mobility group box-1 (HMGB1) translocation from the nucleus to the cytoplasm and the subsequent release of HMGB1 into the supernatant, thus decreasing the activation of Toll-like receptor 4 and the receptor for advanced glycation end products. Collectively, our study reveals a robust RIP1/RIP3-dependent necroptosis pathway in intestinal I/R-induced intestinal injury in vivo and in vitro and suggests that the HMGB1 signalling is highly involved in this process, making it a novel therapeutic target for acute ischaemic intestinal injury.
Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.|Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Shihong
S
Wen
Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China.|Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China.
Yihong
Y
Ling
Department of Anesthesiology, The First Affiliated Hosptial, Zhengzhou University, Zhengzhou, China.
Wenjing
W
Yang
Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Jiantong
J
Shen
Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Cai
C
Li
Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Wentao
W
Deng
Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Weifeng
W
Liu
Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Kexuan
K
Liu
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D061945:Caspase Inhibitors / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D020895:Enterocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D024243:HMGB1 Protein / Q000378:metabolism; D007093:Imidazoles / Q000378:metabolism; D007211:Indoles / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000473:pathology*; D008297:Male; D009336:Necrosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D061945:Caspase Inhibitors; D024243:HMGB1 Protein; D007093:Imidazoles; D007211:Indoles; D053583:Interleukin-1beta; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C507699:necrostatin-1; C000610381:MLKL protein, rat; D011494:Protein Kinases; D053422:Receptor-Interacting Protein Serine-Threonine Kinases
high-mobility group box-1; intestine; ischaemia/reperfusion injury; programmed necrosis
J Immunol. 2003 Apr 1;170(7):3890-7
12646658
Gut. 2013 Jul;62(7):1062-71
22689519
J Cereb Blood Flow Metab. 2008 Sep;28(9):1564-73
18493258
Lab Invest. 2011 Feb;91(2):294-309
20975661
Nat Rev Mol Cell Biol. 2010 Oct;11(10):700-14
20823910
Basic Res Cardiol. 2012 Jul;107(4):270
22553001
Cell. 2012 Jan 20;148(1-2):213-27
22265413
Nature. 2015 Jan 15;517(7534):311-20
25592536
AACN Adv Crit Care. 2007 Apr-Jun;18(2):158-66
17473544
Scand J Immunol. 2005 Jan;61(1):1-9
15644117
Brain Res. 2010 Oct 8;1355:189-94
20682300
J Cell Mol Med. 2011 Sep;15(9):1797-806
21564515
World J Gastroenterol. 2013 Aug 14;19(30):4925-34
23946597
Anesth Analg. 2008 Dec;107(6):1884-91
19020134
Cardiovasc Drugs Ther. 2007 Aug;21(4):227-33
17665295
J Clin Invest. 2000 Sep;106(5):613-4
10974010
Crit Care Med. 2012 Aug;40(8):2438-48
22647410
Gut. 1998 Apr;42(4):530-7
9616316
Lab Invest. 2013 Jul;93(7):792-800
23628899
Annu Rev Immunol. 2011;29:139-62
21219181
Nature. 2011 Sep 14;477(7364):335-9
21921917
Kidney Int. 2012 Apr;81(8):751-61
22237751
Mol Med. 2006 Apr-Jun;12 (4-6):105-14
16953558
Neurobiol Dis. 2014 Aug;68:26-36
24746856
J Surg Res. 2012 Nov;178(1):466-71
22494911
Surgery. 2005 Jan;137(1):85-91
15614285
Arch Surg. 1970 Oct;101(4):478-83
5457245
Nature. 2002 Jul 11;418(6894):191-5
12110890
Nat Rev Mol Cell Biol. 2008 Mar;9(3):231-41
18073771
Cell Res. 2013 Aug;23 (8):994-1006
23835476
Neuropharmacology. 2016 Mar;102:276-94
26647070
Nat Chem Biol. 2005 Jul;1(2):112-9
16408008
Am J Gastroenterol. 2014 Feb;109 (2):279-87
24322838
Cell. 2009 Jun 12;137(6):1100-11
19524512
Proc Natl Acad Sci U S A. 2012 Apr 3;109 (14 ):5322-7
22421439
Ann Surg. 2011 Mar;253(3):561-5
21209591
PLoS One. 2008;3(10):e3428
18927609
Science. 2009 Jul 17;325(5938):332-6
19498109
Proc Natl Acad Sci U S A. 2014 Oct 21;111(42):15072-7
25288762
Semin Vasc Surg. 2010 Mar;23(1):4-8
20298944
J Pathol. 2000 Feb;190(3):255-66
10685060
Surg Today. 2005;35(3):185-95
15772787
Curr Opin Cell Biol. 2010 Apr;22(2):263-8
20045303
Proc Natl Acad Sci U S A. 2013 Jul 16;110(29):12024-9
23818611
Am J Physiol Cell Physiol. 2006 Apr;290(4):C990-9
16282196
Shock. 2012 Oct;38(4):411-9
22777122
Hepatology. 1995 May;21(5):1465-8
7737654
Cell Death Differ. 2010 Jun;17(6):922-30
20010783
Cell. 2012 Jul 20;150(2):339-50
22817896
World J Gastroenterol. 2015 Jul 21;21(27):8314-25
26217083
Cardiovasc Res. 2014 Jul 15;103(2):206-16
24920296
Dig Dis Sci. 2004 Sep;49(9):1359-77
15481305
J Surg Res. 2006 Mar;131(1):58-63
16325857
Hepatology. 2013 Jan;57(1):373-84
22821628