Liver Ischemia Reperfusion Injury, Enhanced by Trained Immunity, Is Attenuated in Caspase 1/Caspase 11 Double Gene Knockout Mice
Ischemia reperfusion injury (IRI) during liver transplantation increases morbidity and contributes to allograft dysfunction. There are no therapeutic strategies to mitigate IRI. We examined a novel hypothesis: caspase 1 and caspase 11 serve as danger-associated molecular pattern (DAMPs) sensors in I...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-10-01
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| Series: | Pathogens |
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| Online Access: | https://www.mdpi.com/2076-0817/9/11/879 |
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| author | Alexander M. Fagenson Keman Xu Fatma Saaoud Gayani Nanayakkara Nirag C. Jhala Lu Liu Charles Drummer Yu Sun Kwan N. Lau Antonio Di Carlo Xiaohua Jiang Hong Wang Sunil S. Karhadkar Xiaofeng Yang |
| author_facet | Alexander M. Fagenson Keman Xu Fatma Saaoud Gayani Nanayakkara Nirag C. Jhala Lu Liu Charles Drummer Yu Sun Kwan N. Lau Antonio Di Carlo Xiaohua Jiang Hong Wang Sunil S. Karhadkar Xiaofeng Yang |
| author_sort | Alexander M. Fagenson |
| collection | DOAJ |
| description | Ischemia reperfusion injury (IRI) during liver transplantation increases morbidity and contributes to allograft dysfunction. There are no therapeutic strategies to mitigate IRI. We examined a novel hypothesis: caspase 1 and caspase 11 serve as danger-associated molecular pattern (DAMPs) sensors in IRI. By performing microarray analysis and using caspase 1/caspase 11 double-knockout (Casp DKO) mice, we show that the canonical and non-canonical inflammasome regulators are upregulated in mouse liver IRI. Ischemic pre (IPC)- and post-conditioning (IPO) induce upregulation of the canonical and non-canonical inflammasome regulators. Trained immunity (TI) regulators are upregulated in IPC and IPO. Furthermore, caspase 1 is activated during liver IRI, and Casp DKO attenuates liver IRI. Casp DKO maintained normal liver histology via decreased DNA damage. Finally, the decreased TUNEL assay-detected DNA damage is the underlying histopathological and molecular mechanisms of attenuated liver pyroptosis and IRI. In summary, liver IRI induces the upregulation of canonical and non-canonical inflammasomes and TI enzyme pathways. Casp DKO attenuate liver IRI. Development of novel therapeutics targeting caspase 1/caspase 11 and TI may help mitigate injury secondary to IRI. Our findings have provided novel insights on the roles of caspase 1, caspase 11, and inflammasome in sensing IRI derived DAMPs and TI-promoted IRI-induced liver injury. |
| first_indexed | 2024-03-10T15:21:21Z |
| format | Article |
| id | doaj.art-188d6a44e7934e439f89aca295223737 |
| institution | Directory Open Access Journal |
| issn | 2076-0817 |
| language | English |
| last_indexed | 2024-03-10T15:21:21Z |
| publishDate | 2020-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pathogens |
| spelling | doaj.art-188d6a44e7934e439f89aca2952237372023-11-20T18:24:40ZengMDPI AGPathogens2076-08172020-10-0191187910.3390/pathogens9110879Liver Ischemia Reperfusion Injury, Enhanced by Trained Immunity, Is Attenuated in Caspase 1/Caspase 11 Double Gene Knockout MiceAlexander M. Fagenson0Keman Xu1Fatma Saaoud2Gayani Nanayakkara3Nirag C. Jhala4Lu Liu5Charles Drummer6Yu Sun7Kwan N. Lau8Antonio Di Carlo9Xiaohua Jiang10Hong Wang11Sunil S. Karhadkar12Xiaofeng Yang13Department of Surgery, Division of Abdominal Organ Transplant, Lewis Katz School of Medicine, Temple University, 3401 N. Broad Street, Philadelphia, PA 19140, USACenters for Cardiovascular Research, Inflammation, Translational and Clinical Lung Research, Metabolic Disease Research, Thrombosis Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USACenters for Cardiovascular Research, Inflammation, Translational and Clinical Lung Research, Metabolic Disease Research, Thrombosis Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USACenters for Cardiovascular Research, Inflammation, Translational and Clinical Lung Research, Metabolic Disease Research, Thrombosis Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USADepartment of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USACenters for Metabolic Disease Research, Cardiovascular Research and Thrombosis Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USACenters for Cardiovascular Research, Inflammation, Translational and Clinical Lung Research, Metabolic Disease Research, Thrombosis Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USACenters for Cardiovascular Research, Inflammation, Translational and Clinical Lung Research, Metabolic Disease Research, Thrombosis Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USADepartment of Surgery, Division of Abdominal Organ Transplant, Lewis Katz School of Medicine, Temple University, 3401 N. Broad Street, Philadelphia, PA 19140, USADepartment of Surgery, Division of Abdominal Organ Transplant, Lewis Katz School of Medicine, Temple University, 3401 N. Broad Street, Philadelphia, PA 19140, USACenters for Cardiovascular Research, Inflammation, Translational and Clinical Lung Research, Metabolic Disease Research, Thrombosis Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USACenters for Metabolic Disease Research, Cardiovascular Research and Thrombosis Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USADepartment of Surgery, Division of Abdominal Organ Transplant, Lewis Katz School of Medicine, Temple University, 3401 N. Broad Street, Philadelphia, PA 19140, USACenters for Cardiovascular Research, Inflammation, Translational and Clinical Lung Research, Metabolic Disease Research, Thrombosis Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USAIschemia reperfusion injury (IRI) during liver transplantation increases morbidity and contributes to allograft dysfunction. There are no therapeutic strategies to mitigate IRI. We examined a novel hypothesis: caspase 1 and caspase 11 serve as danger-associated molecular pattern (DAMPs) sensors in IRI. By performing microarray analysis and using caspase 1/caspase 11 double-knockout (Casp DKO) mice, we show that the canonical and non-canonical inflammasome regulators are upregulated in mouse liver IRI. Ischemic pre (IPC)- and post-conditioning (IPO) induce upregulation of the canonical and non-canonical inflammasome regulators. Trained immunity (TI) regulators are upregulated in IPC and IPO. Furthermore, caspase 1 is activated during liver IRI, and Casp DKO attenuates liver IRI. Casp DKO maintained normal liver histology via decreased DNA damage. Finally, the decreased TUNEL assay-detected DNA damage is the underlying histopathological and molecular mechanisms of attenuated liver pyroptosis and IRI. In summary, liver IRI induces the upregulation of canonical and non-canonical inflammasomes and TI enzyme pathways. Casp DKO attenuate liver IRI. Development of novel therapeutics targeting caspase 1/caspase 11 and TI may help mitigate injury secondary to IRI. Our findings have provided novel insights on the roles of caspase 1, caspase 11, and inflammasome in sensing IRI derived DAMPs and TI-promoted IRI-induced liver injury.https://www.mdpi.com/2076-0817/9/11/879ischemia reperfusion injurycaspase 1caspase 11inflammasomestrained immunity |
| spellingShingle | Alexander M. Fagenson Keman Xu Fatma Saaoud Gayani Nanayakkara Nirag C. Jhala Lu Liu Charles Drummer Yu Sun Kwan N. Lau Antonio Di Carlo Xiaohua Jiang Hong Wang Sunil S. Karhadkar Xiaofeng Yang Liver Ischemia Reperfusion Injury, Enhanced by Trained Immunity, Is Attenuated in Caspase 1/Caspase 11 Double Gene Knockout Mice Pathogens ischemia reperfusion injury caspase 1 caspase 11 inflammasomes trained immunity |
| title | Liver Ischemia Reperfusion Injury, Enhanced by Trained Immunity, Is Attenuated in Caspase 1/Caspase 11 Double Gene Knockout Mice |
| title_full | Liver Ischemia Reperfusion Injury, Enhanced by Trained Immunity, Is Attenuated in Caspase 1/Caspase 11 Double Gene Knockout Mice |
| title_fullStr | Liver Ischemia Reperfusion Injury, Enhanced by Trained Immunity, Is Attenuated in Caspase 1/Caspase 11 Double Gene Knockout Mice |
| title_full_unstemmed | Liver Ischemia Reperfusion Injury, Enhanced by Trained Immunity, Is Attenuated in Caspase 1/Caspase 11 Double Gene Knockout Mice |
| title_short | Liver Ischemia Reperfusion Injury, Enhanced by Trained Immunity, Is Attenuated in Caspase 1/Caspase 11 Double Gene Knockout Mice |
| title_sort | liver ischemia reperfusion injury enhanced by trained immunity is attenuated in caspase 1 caspase 11 double gene knockout mice |
| topic | ischemia reperfusion injury caspase 1 caspase 11 inflammasomes trained immunity |
| url | https://www.mdpi.com/2076-0817/9/11/879 |
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