A20 promotes Brucella intracellular growth via inhibition of macrophage cell death and activation |
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| Institution: | 1. Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, Jilin University, Changchun 130062, People''s Republic of China;2. Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University, Qilu Hospital, Jinan City, Shandong 250012, People''s Republic of China;1. Institute of Military Veterinary Science, Academy of Military Medical Sciences, Changchun 130122, China;2. Hospital of Stomatology, Jilin University, Changchun 130021, China;1. Department of Transfusion Medicine, Southern Medical University, Guangzhou, China;2. School of Animal Science and Technology, Shihezi University, Shihezi, Xinjiang, China;3. Department of Haematology, University of Cambridge, Cambridge, UK;1. South China Agricultural University, Guangzhou, China;2. National Reference Laboratory for Animal Brucellosis, Department of Inspection Technology Research, China Institute of Veterinary Drug Control, Beijing, China;3. China Animal Disease Control Center, Beijing, China;4. Linyi University, Linyi, China;5. China Animal Husbandry Industy Co.Ltd, Beijing, China;3. Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, D-79104 Freiburg, Germany;4. MRC Centre for Molecular Bacteriology and Infection, Department of Life Sciences, Imperial College London, London SW7 2AZ, United Kingdom;5. Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Sciences, Queen''s University Belfast, Belfast BT9 7BL, Northern Ireland, United Kingdom |
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| Abstract: | The zinc-finger protein A20 has crucial physiological functions as a dual inhibitor of macrophage activation and apoptosis in tumor necrosis factor receptor1 (TNFR1) signaling pathway. Brucella infection can induce A20 expression in macrophages. Here, we hypothesize that A20 promotes Brucella intracellular growth via inhibition of activation and apoptosis of macrophages. To test this hypothesis, we stably incorporated mouse A20-shRNA into the RAW264.7 cells by lentiviral gene transfer to successfully knockdown A20. A20-deficient RAW264.7 cells were subsequently challenged with Brucella abortus and colony formation units (CFUs) of bacteria, TNFα production, NF-kB activation, macrophages apoptosis and cell death were evaluated. The A20 knockdown was shown to effectively promote B. abortus-stimulated TNFα release, NF-kB activation and macrophage cell death, which suppressed B. abortus intracellular replication. Unexpectedly, deficiency of A20 failed to lead to B. abortus-induced macrophage apoptosis. A20 deficiency coupled NF-kB inhibition promoted caspase-8 dependent B. abortus-induced macrophage apoptosis. These findings provide a novel mechanism by which Brucella intracellular growth within macrophages occurs through up-regulation of A20 thereby limiting activation and macrophages cell death. |
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| Keywords: | A20 Macrophage Activation |
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