A small molecule binding HMGB1 inhibits caspase-11-mediated lethality in sepsis
Abstract Caspase-11, a cytosolic lipopolysaccharide (LPS) receptor, mediates lethal immune responses and coagulopathy in sepsis, a leading cause of death worldwide with limited therapeutic options. We previously showed that over-activation of caspase-11 is driven by hepatocyte-released high mobility...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2021-04-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-021-03652-5 |
| _version_ | 1818446626173222912 |
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| author | Xiangyu Wang Zhaozheng Li Yang Bai Rui Zhang Ran Meng Fangping Chen Haichao Wang Timothy R. Billiar Xianzhong Xiao Ben Lu Yiting Tang |
| author_facet | Xiangyu Wang Zhaozheng Li Yang Bai Rui Zhang Ran Meng Fangping Chen Haichao Wang Timothy R. Billiar Xianzhong Xiao Ben Lu Yiting Tang |
| author_sort | Xiangyu Wang |
| collection | DOAJ |
| description | Abstract Caspase-11, a cytosolic lipopolysaccharide (LPS) receptor, mediates lethal immune responses and coagulopathy in sepsis, a leading cause of death worldwide with limited therapeutic options. We previously showed that over-activation of caspase-11 is driven by hepatocyte-released high mobility group box 1 (HMGB1), which delivers extracellular LPS into the cytosol of host cells during sepsis. Using a phenotypic screening strategy with recombinant HMGB1 and peritoneal macrophages, we discovered that FeTPPS, a small molecule selectively inhibits HMGB1-mediated caspase-11 activation. The physical interaction between FeTPPS and HMGB1 disrupts the HMGB1-LPS binding and decreases the capacity of HMGB1 to induce lysosomal rupture, leading to the diminished cytosolic delivery of LPS. Treatment of FeTPPS significantly attenuates HMGB1- and caspase-11-mediated immune responses, organ damage, and lethality in endotoxemia and bacterial sepsis. These findings shed light on the development of HMGB1-targeting therapeutics for lethal immune disorders and might open a new avenue to treat sepsis. |
| first_indexed | 2024-12-14T19:50:43Z |
| format | Article |
| id | doaj.art-d6dd62ae957f459097ce62b8c52b0d2b |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-12-14T19:50:43Z |
| publishDate | 2021-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-d6dd62ae957f459097ce62b8c52b0d2b2022-12-21T22:49:26ZengNature Publishing GroupCell Death and Disease2041-48892021-04-0112411410.1038/s41419-021-03652-5A small molecule binding HMGB1 inhibits caspase-11-mediated lethality in sepsisXiangyu Wang0Zhaozheng Li1Yang Bai2Rui Zhang3Ran Meng4Fangping Chen5Haichao Wang6Timothy R. Billiar7Xianzhong Xiao8Ben Lu9Yiting Tang10Department of Hematology and Critical Care Medicine, The 3rd Xiangya Hospital, Central South UniversityDepartment of Hematology and Critical Care Medicine, The 3rd Xiangya Hospital, Central South UniversityDepartment of Hematology and Critical Care Medicine, The 3rd Xiangya Hospital, Central South UniversityDepartment of Hematology and Critical Care Medicine, The 3rd Xiangya Hospital, Central South UniversityDepartment of Hematology and Critical Care Medicine, The 3rd Xiangya Hospital, Central South UniversityDepartment of Hematology and Critical Care Medicine, The 3rd Xiangya Hospital, Central South UniversityThe Feinstein Institute for Medical Research, Northwell HealthDepartment of Surgery, University of Pittsburgh Medical CenterKey Laboratory of sepsis translational medicine of Hunan, Central South UniversityDepartment of Hematology and Critical Care Medicine, The 3rd Xiangya Hospital, Central South UniversityDepartment of Physiology, School of Basic Medical Science, Central South UniversityAbstract Caspase-11, a cytosolic lipopolysaccharide (LPS) receptor, mediates lethal immune responses and coagulopathy in sepsis, a leading cause of death worldwide with limited therapeutic options. We previously showed that over-activation of caspase-11 is driven by hepatocyte-released high mobility group box 1 (HMGB1), which delivers extracellular LPS into the cytosol of host cells during sepsis. Using a phenotypic screening strategy with recombinant HMGB1 and peritoneal macrophages, we discovered that FeTPPS, a small molecule selectively inhibits HMGB1-mediated caspase-11 activation. The physical interaction between FeTPPS and HMGB1 disrupts the HMGB1-LPS binding and decreases the capacity of HMGB1 to induce lysosomal rupture, leading to the diminished cytosolic delivery of LPS. Treatment of FeTPPS significantly attenuates HMGB1- and caspase-11-mediated immune responses, organ damage, and lethality in endotoxemia and bacterial sepsis. These findings shed light on the development of HMGB1-targeting therapeutics for lethal immune disorders and might open a new avenue to treat sepsis.https://doi.org/10.1038/s41419-021-03652-5 |
| spellingShingle | Xiangyu Wang Zhaozheng Li Yang Bai Rui Zhang Ran Meng Fangping Chen Haichao Wang Timothy R. Billiar Xianzhong Xiao Ben Lu Yiting Tang A small molecule binding HMGB1 inhibits caspase-11-mediated lethality in sepsis Cell Death and Disease |
| title | A small molecule binding HMGB1 inhibits caspase-11-mediated lethality in sepsis |
| title_full | A small molecule binding HMGB1 inhibits caspase-11-mediated lethality in sepsis |
| title_fullStr | A small molecule binding HMGB1 inhibits caspase-11-mediated lethality in sepsis |
| title_full_unstemmed | A small molecule binding HMGB1 inhibits caspase-11-mediated lethality in sepsis |
| title_short | A small molecule binding HMGB1 inhibits caspase-11-mediated lethality in sepsis |
| title_sort | small molecule binding hmgb1 inhibits caspase 11 mediated lethality in sepsis |
| url | https://doi.org/10.1038/s41419-021-03652-5 |
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