Novel 1-hydroxy phenothiazinium-based derivative protects against bacterial sepsis by inhibiting AAK1-mediated LPS internalization and caspase-11 signaling
Abstract Sepsis is a life-threatening syndrome with disturbed host responses to severe infections, accounting for the majority of death in hospitalized patients. However, effective medicines are currently scant in clinics due to the poor understanding of the exact underlying mechanism. We previously...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-08-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-05151-7 |
| _version_ | 1828150720874938368 |
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| author | Chuang Yuan Kelong Ai Menghua Xiang Chengliang Xie Mingyi Zhao Ming Wu Hongli Li Yueren Wu Yueqing Cao Can Li Yanjun Zhong Xiaomeng Pei Helen Ka Wai Law Liqian Gao Qicai Xiao Xinyu Yang |
| author_facet | Chuang Yuan Kelong Ai Menghua Xiang Chengliang Xie Mingyi Zhao Ming Wu Hongli Li Yueren Wu Yueqing Cao Can Li Yanjun Zhong Xiaomeng Pei Helen Ka Wai Law Liqian Gao Qicai Xiao Xinyu Yang |
| author_sort | Chuang Yuan |
| collection | DOAJ |
| description | Abstract Sepsis is a life-threatening syndrome with disturbed host responses to severe infections, accounting for the majority of death in hospitalized patients. However, effective medicines are currently scant in clinics due to the poor understanding of the exact underlying mechanism. We previously found that blocking caspase-11 pathway (human orthologs caspase-4/5) is effective to rescue coagulation-induced organ dysfunction and lethality in sepsis models. Herein, we screened our existing chemical pools established in our lab using bacterial outer membrane vesicle (OMV)-challenged macrophages, and found 7-(diethylamino)-1-hydroxy-phenothiazin-3-ylidene-diethylazanium chloride (PHZ-OH), a novel phenothiazinium-based derivative, was capable of robustly dampening caspase-11-dependent pyroptosis. The in-vitro study both in physics and physiology showed that PHZ-OH targeted AP2-associated protein kinase 1 (AAK1) and thus prevented AAK1-mediated LPS internalization for caspase-11 activation. By using a series of gene-modified mice, our in-vivo study further demonstrated that administration of PHZ-OH significantly protected mice against sepsis-associated coagulation, multiple organ dysfunction, and death. Besides, PHZ-OH showed additional protection on Nlrp3 −/− and Casp1 −/− mice but not on Casp11 −/− , Casp1/11 −/− , Msr1 −/− , and AAK1 inhibitor-treated mice. These results suggest the critical role of AAK1 on caspase-11 signaling and may provide a new avenue that targeting AAK1-mediated LPS internalization would be a promising therapeutic strategy for sepsis. In particular, PHZ-OH may serve as a favorable molecule and an attractive scaffold in future medicine development for efficient treatment of bacterial sepsis. |
| first_indexed | 2024-04-11T21:47:16Z |
| format | Article |
| id | doaj.art-f48bfedd5a9046e6a9a2424d7abe9271 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-11T21:47:16Z |
| publishDate | 2022-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-f48bfedd5a9046e6a9a2424d7abe92712022-12-22T04:01:23ZengNature Publishing GroupCell Death and Disease2041-48892022-08-0113811410.1038/s41419-022-05151-7Novel 1-hydroxy phenothiazinium-based derivative protects against bacterial sepsis by inhibiting AAK1-mediated LPS internalization and caspase-11 signalingChuang Yuan0Kelong Ai1Menghua Xiang2Chengliang Xie3Mingyi Zhao4Ming Wu5Hongli Li6Yueren Wu7Yueqing Cao8Can Li9Yanjun Zhong10Xiaomeng Pei11Helen Ka Wai Law12Liqian Gao13Qicai Xiao14Xinyu Yang15Department of Hematology, Xiangya Hospital, Central South UniversityXiangya School of Pharmaceutical Sciences, Central South UniversitySchool of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, and Shenzhen Campus of Sun Yat-sen UniversitySchool of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, and Shenzhen Campus of Sun Yat-sen UniversityDepartment of Hematology, The Seventh Affiliated Hospital, Sun Yat-sen UniversityDepartment of Hematology, Xiangya Hospital, Central South UniversityDepartment of Hematology, Xiangya Hospital, Central South UniversityDepartment of Hematology, Xiangya Hospital, Central South UniversityDepartment of Hematology, Xiangya Hospital, Central South UniversityDepartment of Hematology, Xiangya Hospital, Central South UniversityICU Center in the Second Xiangya Hospital, Central South UniversityDepartment of Health Technology and Informatics, The Hong Kong Polytechnic UniversityDepartment of Health Technology and Informatics, The Hong Kong Polytechnic UniversitySchool of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, and Shenzhen Campus of Sun Yat-sen UniversitySchool of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, and Shenzhen Campus of Sun Yat-sen UniversityDepartment of Hematology, Xiangya Hospital, Central South UniversityAbstract Sepsis is a life-threatening syndrome with disturbed host responses to severe infections, accounting for the majority of death in hospitalized patients. However, effective medicines are currently scant in clinics due to the poor understanding of the exact underlying mechanism. We previously found that blocking caspase-11 pathway (human orthologs caspase-4/5) is effective to rescue coagulation-induced organ dysfunction and lethality in sepsis models. Herein, we screened our existing chemical pools established in our lab using bacterial outer membrane vesicle (OMV)-challenged macrophages, and found 7-(diethylamino)-1-hydroxy-phenothiazin-3-ylidene-diethylazanium chloride (PHZ-OH), a novel phenothiazinium-based derivative, was capable of robustly dampening caspase-11-dependent pyroptosis. The in-vitro study both in physics and physiology showed that PHZ-OH targeted AP2-associated protein kinase 1 (AAK1) and thus prevented AAK1-mediated LPS internalization for caspase-11 activation. By using a series of gene-modified mice, our in-vivo study further demonstrated that administration of PHZ-OH significantly protected mice against sepsis-associated coagulation, multiple organ dysfunction, and death. Besides, PHZ-OH showed additional protection on Nlrp3 −/− and Casp1 −/− mice but not on Casp11 −/− , Casp1/11 −/− , Msr1 −/− , and AAK1 inhibitor-treated mice. These results suggest the critical role of AAK1 on caspase-11 signaling and may provide a new avenue that targeting AAK1-mediated LPS internalization would be a promising therapeutic strategy for sepsis. In particular, PHZ-OH may serve as a favorable molecule and an attractive scaffold in future medicine development for efficient treatment of bacterial sepsis.https://doi.org/10.1038/s41419-022-05151-7 |
| spellingShingle | Chuang Yuan Kelong Ai Menghua Xiang Chengliang Xie Mingyi Zhao Ming Wu Hongli Li Yueren Wu Yueqing Cao Can Li Yanjun Zhong Xiaomeng Pei Helen Ka Wai Law Liqian Gao Qicai Xiao Xinyu Yang Novel 1-hydroxy phenothiazinium-based derivative protects against bacterial sepsis by inhibiting AAK1-mediated LPS internalization and caspase-11 signaling Cell Death and Disease |
| title | Novel 1-hydroxy phenothiazinium-based derivative protects against bacterial sepsis by inhibiting AAK1-mediated LPS internalization and caspase-11 signaling |
| title_full | Novel 1-hydroxy phenothiazinium-based derivative protects against bacterial sepsis by inhibiting AAK1-mediated LPS internalization and caspase-11 signaling |
| title_fullStr | Novel 1-hydroxy phenothiazinium-based derivative protects against bacterial sepsis by inhibiting AAK1-mediated LPS internalization and caspase-11 signaling |
| title_full_unstemmed | Novel 1-hydroxy phenothiazinium-based derivative protects against bacterial sepsis by inhibiting AAK1-mediated LPS internalization and caspase-11 signaling |
| title_short | Novel 1-hydroxy phenothiazinium-based derivative protects against bacterial sepsis by inhibiting AAK1-mediated LPS internalization and caspase-11 signaling |
| title_sort | novel 1 hydroxy phenothiazinium based derivative protects against bacterial sepsis by inhibiting aak1 mediated lps internalization and caspase 11 signaling |
| url | https://doi.org/10.1038/s41419-022-05151-7 |
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