Caspase 6 promotes innate immune activation by functional crosstalk between RIPK1-IκBα axis in liver inflammation
Abstract Background Caspase 6 is an essential regulator in innate immunity, inflammasome activation and host defense. We aimed to characterize the causal mechanism of Caspase 6 in liver sterile inflammatory injury. Methods Human liver tissues were harvested from patients undergoing ischemia-related...
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| Format: | Article |
| Language: | English |
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BMC
2023-10-01
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| Series: | Cell Communication and Signaling |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12964-023-01287-x |
| _version_ | 1797557760909377536 |
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| author | Yuanbang Lin Mingwei Sheng Hua Qin Peng Zhang Chunli Wang Wei Fu Xiangjun Meng Duowei Wang Yachao Hou |
| author_facet | Yuanbang Lin Mingwei Sheng Hua Qin Peng Zhang Chunli Wang Wei Fu Xiangjun Meng Duowei Wang Yachao Hou |
| author_sort | Yuanbang Lin |
| collection | DOAJ |
| description | Abstract Background Caspase 6 is an essential regulator in innate immunity, inflammasome activation and host defense. We aimed to characterize the causal mechanism of Caspase 6 in liver sterile inflammatory injury. Methods Human liver tissues were harvested from patients undergoing ischemia-related hepatectomy to evaluate Caspase 6 expression. Subsequently, we created Caspase 6-knockout (Caspase 6KO) mice to analyze roles and molecular mechanisms of macrophage Caspase 6 in murine models of liver ischemia/reperfusion (IR) injury. Results In human liver biopsies, Caspase 6 expression was positively correlated with more severe histopathological injury and higher serum ALT/AST level at one day postoperatively. Moreover, Caspase 6 was mainly elevated in macrophages but not hepatocytes in ischemic livers. Unlike in controls, the Caspase 6-deficient livers were protected against IR injury, as evidenced by inhibition of inflammation, oxidative stress and iron overload. Disruption of macrophage NF-κB essential modulator (NEMO) in Caspase 6-deficient livers deteriorated liver inflammation and ferroptosis. Mechanistically, Caspase 6 deficiency spurred NEMO-mediated IκBα phosphorylation in macrophage. Then phosphorylated-inhibitor of NF-κBα (p-IκBα) co-localized with receptor-interacting serine/ threonine-protein kinase 1 (RIPK1) in the cytoplasm to degradate RIPK1 under inflammatory conditions. The disruption of RIPK1-IκBα interaction preserved RIPK1 degradation, triggering downstream apoptosis signal-regulating kinase 1 (ASK1) phosphorylation and inciting NIMA-related kinase 7/NOD-like receptor family pyrin domain containing 3 (NEK7/NLRP3) activation in macrophages. Moreover, ablation of macrophage RIPK1 or ASK1 diminished NEK7/NLRP3-driven inflammatory response and dampened hepatocyte ferroptosis by reducing HMGB1 release from macrophages. Conclusions Our findings underscore a novel mechanism of Caspase 6 mediated RIPK1-IκBα interaction in regulating macrophage NEK7/NLRP3 function and hepatocytes ferroptosis, which provides therapeutic targets for clinical liver IR injury. Graphical Abstract Video Abstract |
| first_indexed | 2024-03-10T17:20:58Z |
| format | Article |
| id | doaj.art-f8350b7afad44d4a96f47f32c19ecee4 |
| institution | Directory Open Access Journal |
| issn | 1478-811X |
| language | English |
| last_indexed | 2024-03-10T17:20:58Z |
| publishDate | 2023-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj.art-f8350b7afad44d4a96f47f32c19ecee42023-11-20T10:22:03ZengBMCCell Communication and Signaling1478-811X2023-10-0121111510.1186/s12964-023-01287-xCaspase 6 promotes innate immune activation by functional crosstalk between RIPK1-IκBα axis in liver inflammationYuanbang Lin0Mingwei Sheng1Hua Qin2Peng Zhang3Chunli Wang4Wei Fu5Xiangjun Meng6Duowei Wang7Yachao Hou8Department of General Surgery, Tianjin Medical University General HospitalDepartment of Anesthesiology, Tianjin First Central HospitalCollege of Life Sciences, Nankai UniversityDepartment of General Surgery, Tianjin Medical University General HospitalDepartment of General Surgery, Tianjin Medical University General HospitalDepartment of General Surgery, Tianjin Medical University General HospitalDepartment of General Surgery, Tianjin Medical University General HospitalDepartment of General Surgery, Tianjin Medical University General HospitalDepartment of General Surgery, Tianjin Medical University General HospitalAbstract Background Caspase 6 is an essential regulator in innate immunity, inflammasome activation and host defense. We aimed to characterize the causal mechanism of Caspase 6 in liver sterile inflammatory injury. Methods Human liver tissues were harvested from patients undergoing ischemia-related hepatectomy to evaluate Caspase 6 expression. Subsequently, we created Caspase 6-knockout (Caspase 6KO) mice to analyze roles and molecular mechanisms of macrophage Caspase 6 in murine models of liver ischemia/reperfusion (IR) injury. Results In human liver biopsies, Caspase 6 expression was positively correlated with more severe histopathological injury and higher serum ALT/AST level at one day postoperatively. Moreover, Caspase 6 was mainly elevated in macrophages but not hepatocytes in ischemic livers. Unlike in controls, the Caspase 6-deficient livers were protected against IR injury, as evidenced by inhibition of inflammation, oxidative stress and iron overload. Disruption of macrophage NF-κB essential modulator (NEMO) in Caspase 6-deficient livers deteriorated liver inflammation and ferroptosis. Mechanistically, Caspase 6 deficiency spurred NEMO-mediated IκBα phosphorylation in macrophage. Then phosphorylated-inhibitor of NF-κBα (p-IκBα) co-localized with receptor-interacting serine/ threonine-protein kinase 1 (RIPK1) in the cytoplasm to degradate RIPK1 under inflammatory conditions. The disruption of RIPK1-IκBα interaction preserved RIPK1 degradation, triggering downstream apoptosis signal-regulating kinase 1 (ASK1) phosphorylation and inciting NIMA-related kinase 7/NOD-like receptor family pyrin domain containing 3 (NEK7/NLRP3) activation in macrophages. Moreover, ablation of macrophage RIPK1 or ASK1 diminished NEK7/NLRP3-driven inflammatory response and dampened hepatocyte ferroptosis by reducing HMGB1 release from macrophages. Conclusions Our findings underscore a novel mechanism of Caspase 6 mediated RIPK1-IκBα interaction in regulating macrophage NEK7/NLRP3 function and hepatocytes ferroptosis, which provides therapeutic targets for clinical liver IR injury. Graphical Abstract Video Abstracthttps://doi.org/10.1186/s12964-023-01287-xLiver Ischemia reperfusionInnate immunityFerroptosisCaspase 6 |
| spellingShingle | Yuanbang Lin Mingwei Sheng Hua Qin Peng Zhang Chunli Wang Wei Fu Xiangjun Meng Duowei Wang Yachao Hou Caspase 6 promotes innate immune activation by functional crosstalk between RIPK1-IκBα axis in liver inflammation Cell Communication and Signaling Liver Ischemia reperfusion Innate immunity Ferroptosis Caspase 6 |
| title | Caspase 6 promotes innate immune activation by functional crosstalk between RIPK1-IκBα axis in liver inflammation |
| title_full | Caspase 6 promotes innate immune activation by functional crosstalk between RIPK1-IκBα axis in liver inflammation |
| title_fullStr | Caspase 6 promotes innate immune activation by functional crosstalk between RIPK1-IκBα axis in liver inflammation |
| title_full_unstemmed | Caspase 6 promotes innate immune activation by functional crosstalk between RIPK1-IκBα axis in liver inflammation |
| title_short | Caspase 6 promotes innate immune activation by functional crosstalk between RIPK1-IκBα axis in liver inflammation |
| title_sort | caspase 6 promotes innate immune activation by functional crosstalk between ripk1 iκbα axis in liver inflammation |
| topic | Liver Ischemia reperfusion Innate immunity Ferroptosis Caspase 6 |
| url | https://doi.org/10.1186/s12964-023-01287-x |
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