@article{668ac7b163cb408bbda35d55208e3441,
title = "The Endotoxin Delivery Protein HMGB1 Mediates Caspase-11-Dependent Lethality in Sepsis",
abstract = "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. Caspase-11, a cytosolic LPS receptor, mediates endotoxic shock. Deng and colleagues demonstrate that hepatocyte-released HMGB1 mediates caspase-11-dependent pyroptosis and lethality in sepsis by delivering extracellular LPS into the cytosol of macrophages and endothelial cells, where LPS activates caspase-11.",
keywords = "HMGB1, caspase-11, endotoxemia, inflammasome, pyroptosis, sepsis",
author = "Meihong Deng and Yiting Tang and Wenbo Li and Xiangyu Wang and Rui Zhang and Xianying Zhang and Xin Zhao and Jian Liu and Cheng Tang and Zhonghua Liu and Yongzhuo Huang and Huige Peng and Lehui Xiao and Daolin Tang and Scott, {Melanie J.} and Qingde Wang and Jing Liu and Xianzhong Xiao and Simon Watkins and Jianhua Li and Huan Yang and Haichao Wang and Fangping Chen and Tracey, {Kevin J.} and Billiar, {Timothy R.} and Ben Lu",
note = "Funding Information: The authors thank R. Zhou, A. Bierhaus, and J. Hai for sharing key mouse strains ( Nlrp3 −/− , Ager –/– , Asc –/– , and Gsdmd –/– mice). We thank P. Loughran and H. Liao for their excellent technical support. We thank F. Liu, R. Meng, L. Gu, D. Wang, Y. Lu, and Q. Xue for managing mouse colonies and research assistance. The data presented in this manuscript are tabulated in the main paper and in the supplementary materials. This work was supported by National key scientific project 2015CB910700 (B.L.), National Natural Science Foundation of China (Nos. 81422027 and 81470345 (B.L.), No. 81400149 (Y.T.), and No. 81571879 (T.R.B.), Innovation-driven scientific project of CSU (B.L.), Outstanding young investigator fund of Hunan province (B.L.), and NIH grants RO1GM50441 (T.R.B.), R01GM063075 (H.W.), No. R21AG052912 (Q.W.), No. R01 GM102146 (M.J.S.), and No. R01GM115366 (D.T.). Funding Information: Casp11 fl/fl mice were generated by KOMP repository ( www.komp.org ). The Casp4 mouse strain used for this research project was created from ES cell clone EPD0208_5_H03, obtained from the KOMP Repository ( www.komp.org ) and generated by the Wellcome Trust Sanger Institute (WTSI). Targeting vectors used were generated by the Wellcome Trust Sanger Institute and the Children{\textquoteright}s Hospital Oakland Research Institute as part of the Knockout Mouse Project (3U01HG004080). This strain has the Knockout First, Reporter-tagged insertion with conditional Casp4 (Promoter Driven Cassette) allele, tm1a. The first sliced allele is exposed to the Flp construct (by in vivo Flp breeding) to remove the trapping cassette and render the allele fully conditional. The mouse strain used for this research project, C57BL/6-Tg(CAG-Flpo)1Afst-mucd, identification number 036512-UCD, was obtained from the Mutant Mouse Reginonal Resource Center, a NIH funded strain repository, and was donated by the MMRRC at UC Davis. The original transgenic was donated by Dr. Konstantinos Anastassiadis from Technische Universitaet Dresden. Funding Information: The authors thank R. Zhou, A. Bierhaus, and J. Hai for sharing key mouse strains (Nlrp3−/− Ager–/– Asc–/– and Gsdmd–/– mice). We thank P. Loughran and H. Liao for their excellent technical support. We thank F. Liu, R. Meng, L. Gu, D. Wang, Y. Lu, and Q. Xue for managing mouse colonies and research assistance. The data presented in this manuscript are tabulated in the main paper and in the supplementary materials. This work was supported by National key scientific project 2015CB910700 (B.L.), National Natural Science Foundation of China (Nos. 81422027 and 81470345(B.L.), No. 81400149 (Y.T.), and No. 81571879 (T.R.B.), Innovation-driven scientific project of CSU (B.L.), Outstanding young investigator fund of Hunan province (B.L.), and NIH grants RO1GM50441 (T.R.B.), R01GM063075 (H.W.), No. R21AG052912 (Q.W.), No. R01 GM102146 (M.J.S.), and No. R01GM115366 (D.T.). Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = oct,
day = "16",
doi = "10.1016/j.immuni.2018.08.016",
language = "English",
volume = "49",
pages = "740--753.e7",
journal = "Immunity",
issn = "1074-7613",
number = "4",
}