坏死性下垂
炎症
裂谷1
细胞生物学
程序性细胞死亡
坦克结合激酶1
IκB激酶
TLR4型
信号转导
特里夫
癌症研究
化学
先天免疫系统
免疫学
生物
NF-κB
免疫系统
MAPK/ERK通路
细胞凋亡
生物化学
Toll样受体
MAP激酶激酶激酶
作者
Jieyan Wang,Ying-yi Luan,Erica K. Fan,Melanie J. Scott,Yuehua Li,Timothy R. Billiar,Mark A. Wilson,Yong Jiang,Jie Fan
出处
期刊:Shock
[Lippincott Williams & Wilkins]
日期:2020-09-09
卷期号:55 (3): 338-348
被引量:4
标识
DOI:10.1097/shk.0000000000001632
摘要
Cell necroptosis, a form of regulated inflammatory cell death, is one of the mechanisms that controls cell release of inflammatory mediators from innate immune cells, such as polymorphonuclear neutrophils (PMNs), and critically regulates the progress of inflammation. Cell necroptosis features receptor-interacting protein (RIPK) 1 activation and necroptosome formation. This leads to loss of plasma membrane integrity, the release of cell contents into the extracellular space, and subsequent increased inflammation. Here, we report an intra-PMN mechanism of negative regulation of necroptosis mediated through TBK1/IKKε. Using an in vivo mouse model of intratracheal injection (i.t.) of LPS and in vitro LPS stimulation of mouse PMN, we found that LPS-TLR4 signaling in PMNs activates and phosphorylates TBK1 and IKKε, which in turn suppress LPS-induced formation of the RIPK1-RIPK3-MLKL (necrosome) complex. TBK1 dysfunction by knockdown or inhibitor significantly increases the phosphorylation of RIPK1 (∼67%), RIPK3 (∼68%), and MLKL (∼50%) and promotes RIPK1-RIPK3 and RIPK3-MLKL interactions and increases PMN necroptosis (∼83%) in response to LPS, with subsequent augmented lung inflammation. These findings suggest that the LPS-TLR4-TBK1 axis serves as a negative regulator for PMN necroptosis and might be a therapeutic target for modulating PMN death and inflammation.
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