Oxylipin metabolism is controlled by mitochondrial β-oxidation during bacterial inflammation
Oxylipin metabolism is controlled by mitochondrial β-oxidation during bacterial inflammation
Abstract Oxylipins are potent mediators requiring strict control. How they are removed en masse during infection/inflammation is unknown. Herein, lipopolysaccharide (LPS) dynamically increased their mitochondrial β-oxidation, impacting leukocyte bioactivity. Genetic/pharmacological targeting of CPT1 showed <50 oxylipins were robustly removed by macrophage mitochondria during inflammation in vitro and in vivo. Stable isotope-lipidomics demonstrated secretion-reuptake recycling for 12-HETE and its intermediate metabolites. Oxylipin β?oxidation was uncoupled from oxidative phosphorylation. Transcriptional interrogation of human neonatal sepsis revealed significant upregulation of many candidates, encoding proteins for mitochondrial uptake and β-oxidation of long-chain fatty acyls (ACSL1,3,4, ACADVL, CPT1B, CPT2, HADHB). ACSL1/Acsl1 upregulation was a signature in multiple human/murine macrophage datasets. In summary, mitochondrial β-oxidation is a regulatory metabolic checkpoint for oxylipins during infection. This has implications for patients with CPT1 deficiency, at higher risk of mortality during respiratory infections. We propose that mitochondrial β-oxidation capacity to remove oxylipins during infection may directly influence development of inflammation.
Taylor Philip R、Kotzamanis Konstantinos、Davies Luke C、Kennedy Paul、Rosas Marcela、Jones Simon A、Andrews Robert、Czubala Magdalena A、Meckelmann Sven W、Ghazal Peter、Darley-Usmar Victor、White Daniel、Rodrigues Patricia R S、Benavides Gloria A、Hinz Christine、Deshpande Sumukh、Gurney Mark、Misheva Mariya、Murphy Robert C、O?ˉDonnell Valerie B、Aldrovandi Maceler、Tyrrell Victoria J
Systems Immunity Research Institute and Division of Infection and Immunity, and School of Medicine, Cardiff University||UK Dementia Research Institute at Cardiff, Cardiff UniversitySystems Immunity Research Institute and Division of Infection and Immunity, and School of Medicine, Cardiff UniversitySystems Immunity Research Institute and Division of Infection and Immunity, and School of Medicine, Cardiff UniversityCayman ChemicalSystems Immunity Research Institute and Division of Infection and Immunity, and School of Medicine, Cardiff UniversitySystems Immunity Research Institute and Division of Infection and Immunity, and School of Medicine, Cardiff UniversitySystems Immunity Research Institute and Division of Infection and Immunity, and School of Medicine, Cardiff UniversitySystems Immunity Research Institute and Division of Infection and Immunity, and School of Medicine, Cardiff UniversitySystems Immunity Research Institute and Division of Infection and Immunity, and School of Medicine, Cardiff UniversitySystems Immunity Research Institute and Division of Infection and Immunity, and School of Medicine, Cardiff UniversityDepartment of Pathology, University of Alabama at BirminghamSystems Immunity Research Institute and Division of Infection and Immunity, and School of Medicine, Cardiff UniversitySystems Immunity Research Institute and Division of Infection and Immunity, and School of Medicine, Cardiff UniversityDepartment of Pathology, University of Alabama at BirminghamSystems Immunity Research Institute and Division of Infection and Immunity, and School of Medicine, Cardiff UniversitySystems Immunity Research Institute and Division of Infection and Immunity, and School of Medicine, Cardiff UniversitySystems Immunity Research Institute and Division of Infection and Immunity, and School of Medicine, Cardiff UniversitySystems Immunity Research Institute and Division of Infection and Immunity, and School of Medicine, Cardiff UniversityDepartment of Pharmacology, University of Colorado DenverSystems Immunity Research Institute and Division of Infection and Immunity, and School of Medicine, Cardiff UniversitySystems Immunity Research Institute and Division of Infection and Immunity, and School of Medicine, Cardiff UniversitySystems Immunity Research Institute and Division of Infection and Immunity, and School of Medicine, Cardiff University
基础医学生物化学分子生物学
Taylor Philip R,Kotzamanis Konstantinos,Davies Luke C,Kennedy Paul,Rosas Marcela,Jones Simon A,Andrews Robert,Czubala Magdalena A,Meckelmann Sven W,Ghazal Peter,Darley-Usmar Victor,White Daniel,Rodrigues Patricia R S,Benavides Gloria A,Hinz Christine,Deshpande Sumukh,Gurney Mark,Misheva Mariya,Murphy Robert C,O?ˉDonnell Valerie B,Aldrovandi Maceler,Tyrrell Victoria J.Oxylipin metabolism is controlled by mitochondrial β-oxidation during bacterial inflammation[EB/OL].(2025-03-28)[2025-05-22].https://www.biorxiv.org/content/10.1101/2020.08.17.252007.点此复制
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