Inflammatory adhesion mediates myocardial segmental necroptosis induced by mixed lineage kinase domain-like protein in acute myocardial infarction
Abstract Purpose Cardiomyocyte death is a major cytopathologic response in acute myocardial infarction (AMI) and involves complex inflammatory interactions. Although existing reports indicating that mixed lineage kinase domain-like protein (MLKL) is involved in macrophage necroptosis and inflammasom...
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BMC
2025-01-01
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| Series: | Cell Communication and Signaling |
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| Online Access: | https://doi.org/10.1186/s12964-025-02031-3 |
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| author | Lijiang Wei Naifu Wan Wentong Zhu Chenchen Liu Zeyu Chen Wuwei Rong Lujun Zhang Meifeng Xie Yueqi Qin Ting Sun Qing Jing Ankang Lyu |
| author_facet | Lijiang Wei Naifu Wan Wentong Zhu Chenchen Liu Zeyu Chen Wuwei Rong Lujun Zhang Meifeng Xie Yueqi Qin Ting Sun Qing Jing Ankang Lyu |
| author_sort | Lijiang Wei |
| collection | DOAJ |
| description | Abstract Purpose Cardiomyocyte death is a major cytopathologic response in acute myocardial infarction (AMI) and involves complex inflammatory interactions. Although existing reports indicating that mixed lineage kinase domain-like protein (MLKL) is involved in macrophage necroptosis and inflammasome activation, the downstream mechanism of MLKL in necroptosis remain poorly characterized in AMI. Methods MLKL knockout mice (MLKLKO), RIPK3 knockout mice (RIPK3KO), and macrophage-specific MLKL conditional knockout mice (MLKLM−KO) were established. AMI was induced by coronary artery ligation. The role of MLKL in regulating myocardial morphological necroptosis was evaluated using immunofluorescence staining, flow cytometry, qRT-PCR, Western blot, CCK-8 assay, and ELISA. Results Our findings revealed that myocardial segmental necroptosis (MSN), a unique morphological characteristics of cell death observed post-AMI, was promoted by intercellular inflammatory adhesion mediated by MLKL. The key features of MSN included localized cytomembrane perforation, segmental attenuation of myofilaments, MLKL-mediated filling, and macrophage inflammatory adhesion. In a mouse model of AMI, we observed MSN, which was absent in immunosuppressed mice. Pharmacological depletion of macrophages or genetic knockout of macrophage-specific MLKL (MLKLM−KO) reduced the occurrence of MSN. This reduction was reversed upon reinfusion of wild-type macrophages. Additionally, myocardial injury was significantly ameliorated in MLKLM−KO mice following AMI. In a macrophage-cardiomyocyte co-culture system, MLKLM−KO attenuated hypoxia-induced MSN and inhibited macrophage-mediated inflammatory adhesion. Furthermore, MLKL was found to trigger the formation of membrane pores and the polymerization of integrin αvβ1, thereby enhancing inflammatory adhesion in the co-culture system. Notably, MLKL-enhanced inflammatory adhesion was not entirely dependent on RIPK3. Conclusion Our study demonstrates that MLKL is directly involved in myocardial segmental necroptosis by interacting with macrophages through inflammatory adhesion, and possibly independently of RIPK3. |
| format | Article |
| id | doaj-art-03f4ec01d5404b558debc938650d074f |
| institution | Kabale University |
| issn | 1478-811X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
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| series | Cell Communication and Signaling |
| spelling | doaj-art-03f4ec01d5404b558debc938650d074f2025-01-19T12:32:59ZengBMCCell Communication and Signaling1478-811X2025-01-0123111910.1186/s12964-025-02031-3Inflammatory adhesion mediates myocardial segmental necroptosis induced by mixed lineage kinase domain-like protein in acute myocardial infarctionLijiang Wei0Naifu Wan1Wentong Zhu2Chenchen Liu3Zeyu Chen4Wuwei Rong5Lujun Zhang6Meifeng Xie7Yueqi Qin8Ting Sun9Qing Jing10Ankang Lyu11Department of Vascular & Cardiology, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Vascular & Cardiology, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Vascular & Cardiology, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Vascular & Cardiology, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Vascular & Cardiology, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Vascular & Cardiology, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineCAS Key Laboratory of Tissue Microenvironment and Tumor, Innovation Center for Intervention of Chronic Disease and Promotion of Health, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of SciencesCAS Key Laboratory of Tissue Microenvironment and Tumor, Innovation Center for Intervention of Chronic Disease and Promotion of Health, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of SciencesDepartment of General Medicine, Yongchuan Hospital, Chongqing Medical UniversityDepartment of Cardiology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineCAS Key Laboratory of Tissue Microenvironment and Tumor, Innovation Center for Intervention of Chronic Disease and Promotion of Health, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of SciencesDepartment of Vascular & Cardiology, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineAbstract Purpose Cardiomyocyte death is a major cytopathologic response in acute myocardial infarction (AMI) and involves complex inflammatory interactions. Although existing reports indicating that mixed lineage kinase domain-like protein (MLKL) is involved in macrophage necroptosis and inflammasome activation, the downstream mechanism of MLKL in necroptosis remain poorly characterized in AMI. Methods MLKL knockout mice (MLKLKO), RIPK3 knockout mice (RIPK3KO), and macrophage-specific MLKL conditional knockout mice (MLKLM−KO) were established. AMI was induced by coronary artery ligation. The role of MLKL in regulating myocardial morphological necroptosis was evaluated using immunofluorescence staining, flow cytometry, qRT-PCR, Western blot, CCK-8 assay, and ELISA. Results Our findings revealed that myocardial segmental necroptosis (MSN), a unique morphological characteristics of cell death observed post-AMI, was promoted by intercellular inflammatory adhesion mediated by MLKL. The key features of MSN included localized cytomembrane perforation, segmental attenuation of myofilaments, MLKL-mediated filling, and macrophage inflammatory adhesion. In a mouse model of AMI, we observed MSN, which was absent in immunosuppressed mice. Pharmacological depletion of macrophages or genetic knockout of macrophage-specific MLKL (MLKLM−KO) reduced the occurrence of MSN. This reduction was reversed upon reinfusion of wild-type macrophages. Additionally, myocardial injury was significantly ameliorated in MLKLM−KO mice following AMI. In a macrophage-cardiomyocyte co-culture system, MLKLM−KO attenuated hypoxia-induced MSN and inhibited macrophage-mediated inflammatory adhesion. Furthermore, MLKL was found to trigger the formation of membrane pores and the polymerization of integrin αvβ1, thereby enhancing inflammatory adhesion in the co-culture system. Notably, MLKL-enhanced inflammatory adhesion was not entirely dependent on RIPK3. Conclusion Our study demonstrates that MLKL is directly involved in myocardial segmental necroptosis by interacting with macrophages through inflammatory adhesion, and possibly independently of RIPK3.https://doi.org/10.1186/s12964-025-02031-3Myocardial segmental necroptosisMLKLInflammatoryMacrophagesAcute myocardial infarction |
| spellingShingle | Lijiang Wei Naifu Wan Wentong Zhu Chenchen Liu Zeyu Chen Wuwei Rong Lujun Zhang Meifeng Xie Yueqi Qin Ting Sun Qing Jing Ankang Lyu Inflammatory adhesion mediates myocardial segmental necroptosis induced by mixed lineage kinase domain-like protein in acute myocardial infarction Cell Communication and Signaling Myocardial segmental necroptosis MLKL Inflammatory Macrophages Acute myocardial infarction |
| title | Inflammatory adhesion mediates myocardial segmental necroptosis induced by mixed lineage kinase domain-like protein in acute myocardial infarction |
| title_full | Inflammatory adhesion mediates myocardial segmental necroptosis induced by mixed lineage kinase domain-like protein in acute myocardial infarction |
| title_fullStr | Inflammatory adhesion mediates myocardial segmental necroptosis induced by mixed lineage kinase domain-like protein in acute myocardial infarction |
| title_full_unstemmed | Inflammatory adhesion mediates myocardial segmental necroptosis induced by mixed lineage kinase domain-like protein in acute myocardial infarction |
| title_short | Inflammatory adhesion mediates myocardial segmental necroptosis induced by mixed lineage kinase domain-like protein in acute myocardial infarction |
| title_sort | inflammatory adhesion mediates myocardial segmental necroptosis induced by mixed lineage kinase domain like protein in acute myocardial infarction |
| topic | Myocardial segmental necroptosis MLKL Inflammatory Macrophages Acute myocardial infarction |
| url | https://doi.org/10.1186/s12964-025-02031-3 |
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