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

被引：485

作者：

Deng, Meihong ^{[3
]}

Tang, Yiting ^{[4
]}

Li, Wenbo ^{[1
,2
,5
]}

Wang, Xiangyu ^{[1
,2
,5
,6
]}

Zhang, Rui ^{[1
,2
,5
,6
]}

Zhang, Xianying ^{[1
,2
,5
,6
]}

Zhao, Xin ^{[1
,2
,5
,6
]}

Liu, Jian ^{[1
,2
,5
,6
]}

Tang, Cheng ^{[7
]}

Liu, Zhonghua ^{[7
]}

Huang, Yongzhuo ^{[8
]}

Peng, Huige ^{[8
]}

Xiao, Lehui ^{[9
]}

Tang, Daolin ^{[3
]}

Scott, Melanie J. ^{[3
]}

Wang, Qingde ^{[3
]}

Liu, Jing ^{[1
,2
]}

Xiao, Xianzhong ^{[6
]}

Watkins, Simon ^{[10
]}

Li, Jianhua ^{[11
]}

Yang, Huan ^{[11
]}

Wang, Haichao ^{[12
]}

Chen, Fangping ^{[1
,2
]}

Tracey, Kevin J. ^{[11
]}

Billiar, Timothy R. ^{[3
]}

Lu, Ben ^{[1
,2
,5
,6
]}

机构：

[1] Cent South Univ, Xiangya Hosp 3, Dept Hematol, Changsha 410000, Hunan, Peoples R China

[2] Cent South Univ, Xiangya Hosp 3, Key Lab Nonresolving Inflammat & Canc Hunan Prov, Changsha 410000, Hunan, Peoples R China

[3] Univ Pittsburgh, Sch Med, Dept Surg, Pittsburgh, PA 15213 USA

[4] Cent South Univ, Sch Basic Med Sci, Dept Physiol, Changsha 410000, Hunan, Peoples R China

[5] Cent South Univ, Sch Biol Sci & Technol, Key Lab Med Genet, Changsha 410000, Hunan, Peoples R China

[6] Cent South Univ, Key Lab Sepsis Translat Med Hunan, Changsha 410000, Hunan, Peoples R China

[7] Hunan Normal Univ, Coll Life Sci, Changsha 410081, Hunan, Peoples R China

[8] Chinese Acad Sci, Shanghai Inst Mat Med, 501 Hai Ke Rd, Shanghai 201203, Peoples R China

[9] Nankai Univ, Coll Chem, Tianjin 300073, Peoples R China

[10] Univ Pittsburgh, Sch Med, Ctr Biol Imaging, Pittsburgh, PA 15213 USA

[11] Northwell Hlth, Feinstein Inst Med Res, Lab Biomed Sci, 350 Community Dr, Manhasset, NY 11030 USA

[12] Northwell Hlth, North Shore Univ Hosp, Dept Emergency Med, 350 Community Dr, Manhasset, NY 11030 USA

来源：

IMMUNITY | 2018年 / 49卷 / 04期

基金：

中国国家自然科学基金;

关键词：

NONCANONICAL INFLAMMASOME ACTIVATION; GROUP BOX 1; GASDERMIN D; ALARMIN HMGB1; RELEASE; LIPOPOLYSACCHARIDE; RECEPTOR; LPS; PYROPTOSIS; BINDING;

D O I：

10.1016/j.immuni.2018.08.016

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

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.

引用

页码：740 / +

页数：21

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