Open AccessNecroptosis is a key mediator of enterocytes loss in intestinal ischaemia/reperfusion injury
Author(s) -
Wen Shihong,
Ling Yihong,
Yang Wenjing,
Shen Jiantong,
Li Cai,
Deng Wentao,
Liu Weifeng,
Liu Kexuan
Publication year - 2017
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.12987
Subject(s) - necroptosis , programmed cell death , microbiology and biotechnology , apoptosis , biology , necrosis , caspase , ripk1 , kinase , signal transduction , tumor necrosis factor alpha , cancer research , immunology , biochemistry , genetics
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 ( RIP 1/3) 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 RIP 1 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 ( HMGB 1) translocation from the nucleus to the cytoplasm and the subsequent release of HMGB 1 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 RIP 1/ RIP 3‐dependent necroptosis pathway in intestinal I/R‐induced intestinal injury in vivo and in vitro and suggests that the HMGB 1 signalling is highly involved in this process, making it a novel therapeutic target for acute ischaemic intestinal injury.