Liver Ischemia Reperfusion Injury, Enhanced by Trained Immunity, Is Attenuated in Caspase 1/Caspase 11 Double Gene Knockout Mice
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
Affiliations
Alexander M. Fagenson
Department of Surgery, Division of Abdominal Organ Transplant, Lewis Katz School of Medicine, Temple University, 3401 N. Broad Street, Philadelphia, PA 19140, USA
Keman Xu
Centers for Cardiovascular Research, Inflammation, Translational and Clinical Lung Research, Metabolic Disease Research, Thrombosis Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
Fatma Saaoud
Centers for Cardiovascular Research, Inflammation, Translational and Clinical Lung Research, Metabolic Disease Research, Thrombosis Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
Gayani Nanayakkara
Centers for Cardiovascular Research, Inflammation, Translational and Clinical Lung Research, Metabolic Disease Research, Thrombosis Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
Nirag C. Jhala
Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
Lu Liu
Centers for Metabolic Disease Research, Cardiovascular Research and Thrombosis Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
Charles Drummer
Centers for Cardiovascular Research, Inflammation, Translational and Clinical Lung Research, Metabolic Disease Research, Thrombosis Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
Yu Sun
Centers for Cardiovascular Research, Inflammation, Translational and Clinical Lung Research, Metabolic Disease Research, Thrombosis Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
Kwan N. Lau
Department of Surgery, Division of Abdominal Organ Transplant, Lewis Katz School of Medicine, Temple University, 3401 N. Broad Street, Philadelphia, PA 19140, USA
Antonio Di Carlo
Department of Surgery, Division of Abdominal Organ Transplant, Lewis Katz School of Medicine, Temple University, 3401 N. Broad Street, Philadelphia, PA 19140, USA
Xiaohua Jiang
Centers for Cardiovascular Research, Inflammation, Translational and Clinical Lung Research, Metabolic Disease Research, Thrombosis Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
Hong Wang
Centers for Metabolic Disease Research, Cardiovascular Research and Thrombosis Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
Sunil S. Karhadkar
Department of Surgery, Division of Abdominal Organ Transplant, Lewis Katz School of Medicine, Temple University, 3401 N. Broad Street, Philadelphia, PA 19140, USA
Xiaofeng Yang
Centers for Cardiovascular Research, Inflammation, Translational and Clinical Lung Research, Metabolic Disease Research, Thrombosis Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
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.
