LPS Induces Active HMGB1 Release From Hepatocytes Into Exosomes Through the Coordinated Activities of TLR4 and Caspase-11/GSDMD Signaling

被引:115
作者
Li, Wenbo [1 ,2 ]
Deng, Meihong [2 ]
Loughran, Patricia A. [2 ,3 ]
Yang, Muqing [2 ,4 ]
Lin, Minjie [2 ,5 ]
Yang, Chenxuan [2 ,6 ]
Gao, Wentao [2 ]
Jin, Shuqing [2 ,7 ]
Li, Shilai [2 ,8 ]
Cai, Jingjing [2 ,9 ]
Lu, Ben [10 ]
Billiar, Timothy R. [2 ,11 ]
Scott, Melanie J. [2 ,11 ]
机构
[1] Cent South Univ, Xiangya Hosp 2, Dept Burn & Plast Surg, Changsha, Peoples R China
[2] Univ Pittsburgh, Dept Surg, Pittsburgh, PA 15260 USA
[3] Univ Pittsburgh, Ctr Biol Imaging, Pittsburgh, PA USA
[4] Tongji Univ, Peoples Hosp 10, Dept Surg, Shanghai, Peoples R China
[5] Cent South Univ, Clin Skills Training Ctr, Xiangya Hosp 2, Changsha, Peoples R China
[6] Tsinghua Univ, Sch Med, Beijing, Peoples R China
[7] Tongji Univ, Shanghai East Hosp, Dept Anesthesiol, Shanghai, Peoples R China
[8] Guangxi Med Univ, Affiliated Hosp 1, Dept Emergency, Nanning, Peoples R China
[9] Cent South Univ, Xiangya Hosp 3, Dept Cardiol, Changsha, Peoples R China
[10] Cent South Univ, Xiangya Hosp 3, Dept Hematopathol, Changsha, Peoples R China
[11] Univ Pittsburgh, Pittsburgh Liver Res Ctr, Pittsburgh, PA USA
关键词
gasdermin D (GsdmD); endotoxemia; caspase-11; extracellular vesicles; calcium; innate immunity; GROUP BOX 1; MOBILITY GROUP BOX-1; EXTRACELLULAR VESICLES; INFLAMMATORY CASPASES; REPERFUSION INJURY; RECEPTOR; LIPOPOLYSACCHARIDE; ACTIVATION; ISCHEMIA; SEPSIS;
D O I
10.3389/fimmu.2020.00229
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
High-mobility group box-1 (HMGB1), a ubiquitous nuclear protein, acts as a late mediator of lethality when released extracellularly during sepsis. The major source of circulating HMGB1 in sepsis is hepatocytes. However, the mechanism of HMGB1 release of hepatocytes during sepsis is not very clear. We have previously shown that bacterial endotoxin [lipopolysaccharide (LPS)] sensing pathways, including Toll-like receptor (TLR)4 and caspase-11, regulate hepatocyte HMGB1 release in response to LPS. Here, we report the novel function of caspase-11 and gasdermin D (GsdmD) in LPS-induced active HMGB1 released from hepatocytes. HMGB1 release during endotoxemia was caspase-11/GsdmD dependent via an active way in vivo and in vitro. Caspase-11/GsdmD was responsible for HMGB1 translocation from nucleus to the cytoplasm via calcium changing-induced phosphorylation of calcium-calmodulin kinase kinase (camkk)beta during endotoxemia. Cleaved GsdmD accumulated on the endoplasmic reticulum, suggesting this may lead to calcium leak and intracellular calcium increase. Furthermore, we investigated that exosome was an important pathway for HMGB1 release from hepatocytes; this process was dependent on TLR4, independent of caspase-11 and GsdmD in vivo and in vitro. These findings provide a novel mechanism that TLR4 signaling results in an increase in caspase-11 expression, as well as increased exosome release, while caspase-11/GsdmD activation/cleavage leads to accumulation of HMGB1 in the cytoplasm through a process associated with the release of calcium from the endoplasmic reticulum and camkk beta activation.
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页数:13
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