The Endotoxin Delivery Protein HMGB1 Mediates Caspase-11-Dependent Lethality in Sepsis

doi:10.1016/j.immuni.2018.08.016

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药物制剂研究中心

	The Endotoxin Delivery Protein HMGB1 Mediates Caspase-11-Dependent Lethality in Sepsis
	Deng, Meihong 10; Tang, Yiting 9; Li, Wenbo 8,11,12; Wang, Xiangyu 7,8,11,12; Zhang, Rui 7,8,11,12; Zhang, Xianying 7,8,11,12; Zhao, Xin 7,8,11,12; Liu, Jian 7,8,11,12; Tang, Cheng 6; Liu, Zhonghua 6
刊名	IMMUNITY
	2018-10-16
卷号	49 期号:4 页码:740-+
ISSN号	1074-7613
DOI	10.1016/j.immuni.2018.08.016
文献子类	Article
英文摘要	Caspase-11, a cytosolic endotoxin (lipopolysaccharide: LPS) receptor, mediates pyroptosis, a lytic form of cell death. Caspase-11-dependent pyroptosis mediates lethality in endotoxemia, but it is unclear how LPS is delivered into the cytosol for the activation of caspase-11. Here we discovered that hepatocyte-released high mobility group box 1 (HMGB1) was required for caspase-11-dependent pyroptosis and lethality in endotoxemia and bacterial sepsis. Mechanistically, hepatocyte-released HMGB1 bound LPS and targeted its internalization into the lysosomes of macrophages and endothelial cells via the receptor for advanced glycation end-products (RAGE). Subsequently, HMGB1 permeabilized the phospholipid bilayer in the acidic environment of lysosomes. This resulted in LPS leakage into the cytosol and caspase-11 activation. Depletion of hepatocyte HMGB1, inhibition of hepatocyte HMGB1 release, neutralizing extracellular HMGB1, or RAGE deficiency prevented caspase-11-dependent pyroptosis and death in endotoxemia and bacterial sepsis. These findings indicate that HMGB1 interacts with LPS to mediate caspase-11-dependent pyroptosis in lethal sepsis.
资助项目	National key scientific project[2015CB910700] ; National Natural Science Foundation of China[81422027] ; National Natural Science Foundation of China[81470345] ; National Natural Science Foundation of China[81400149] ; National Natural Science Foundation of China[81571879] ; Innovation-driven scientific project of CSU[00000000] ; Outstanding young investigator fund of Hunan province[00000000] ; NIH[RO1GM50441] ; NIH[R01GM063075] ; NIH[R21AG052912] ; NIH[R01 GM102146] ; NIH[R01GM115366]
WOS关键词	NONCANONICAL INFLAMMASOME ACTIVATION ; GROUP BOX-1 PROTEIN ; GASDERMIN D ; NLRP3 INFLAMMASOME ; INTRACELLULAR LPS ; ALARMIN HMGB1 ; RELEASE ; LIPOPOLYSACCHARIDE ; RECEPTOR ; PYROPTOSIS
WOS研究方向	Immunology
语种	英语
出版者	CELL PRESS
WOS记录号	WOS:000447386700018
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279531]
专题	药物制剂研究中心
通讯作者	Billiar, Timothy R.; Lu, Ben
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, 501 Hai Ke Rd, Shanghai 201203, Peoples R China; 2.Northwell Hlth, North Shore Univ Hosp, Dept Emergency Med, 350 Community Dr, Manhasset, NY 11030 USA 3.Northwell Hlth, Feinstein Inst Med Res, Lab Biomed Sci, 350 Community Dr, Manhasset, NY 11030 USA; 4.Univ Pittsburgh, Sch Med, Ctr Biol Imaging, Pittsburgh, PA 15213 USA; 5.Nankai Univ, Coll Chem, Tianjin 300073, Peoples R China; 6.Hunan Normal Univ, Coll Life Sci, Changsha 410081, Hunan, Peoples R China; 7.Cent S Univ, Key Lab Sepsis Translat Med Hunan, Changsha 410000, Hunan, Peoples R China; 8.Cent S Univ, Sch Biol Sci & Technol, Key Lab Med Genet, Changsha 410000, Hunan, Peoples R China; 9.Cent S Univ, Sch Basic Med Sci, Dept Physiol, Changsha 410000, Hunan, Peoples R China; 10.Univ Pittsburgh, Sch Med, Dept Surg, Pittsburgh, PA 15213 USA;
推荐引用方式 GB/T 7714	Deng, Meihong,Tang, Yiting,Li, Wenbo,et al. The Endotoxin Delivery Protein HMGB1 Mediates Caspase-11-Dependent Lethality in Sepsis[J]. IMMUNITY,2018,49(4):740-+.
APA	Deng, Meihong.,Tang, Yiting.,Li, Wenbo.,Wang, Xiangyu.,Zhang, Rui.,...&Lu, Ben.(2018).The Endotoxin Delivery Protein HMGB1 Mediates Caspase-11-Dependent Lethality in Sepsis.IMMUNITY,49(4),740-+.
MLA	Deng, Meihong,et al."The Endotoxin Delivery Protein HMGB1 Mediates Caspase-11-Dependent Lethality in Sepsis".IMMUNITY 49.4(2018):740-+.