MerTK negatively regulates Staphylococcus aureus induced inflammatory response via SOCS1/SOCS3 and Mal |
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| Affiliation: | 1. Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, People''s Republic of China;2. College of Veterinary Sciences, The University of Agriculture Peshawar, Pakistan;1. Department of Biological Sciences, Université du Québec à Montréal, Montréal, Canada;2. Department of Chemistry, Université du Québec à Montréal, Montréal, Canada;3. The Swine and Poultry Infectious Diseases Research Centre (CRIPA), Saint-Hyacinthe, Canada;4. Quebec Network for Research on Protein Function, Engineering, and Applications, PROTEO, Québec, Canada;5. Centre d''Excellence en Recherche sur les Maladies Orphelines-Fondation Courtois (CERMO-FC), Université du Québec à Montréal, Montréal, Canada;6. Faculté de Médecine Vétérinaire, Université de Montréal, Saint-Hyacinthe, Canada;1. Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China;2. Key Laboratory of Nephrology, National Health Commission and Guangdong Province, Guangzhou, Guangdong, 510080, China;3. Department of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510080, China;4. Clinical Trials Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China;1. Laboratory of Experimental Pathology, School of Medicine, Pontifical Catholic University of Parana – PUCPR, R. Imaculada Conceição, 1155 - Prado Velho, Curitiba, PR, Brazil;2. Department of Medical Pathology, Federal University of Parana – UFPR, R. Padre Camargo, 280 – Alto da Glória, Curitiba, PR, Brazil;3. Virology Laboratory, Infectious Diseases Division, Federal University of Parana – UFPR, R. Padre Camargo, 280 – Alto da Gloria, Curitiba, PR, Brazil;1. Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, Campinas, SP, Brazil;2. Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA;3. Faculty of Pharmaceutical Sciences, State University of Campinas, Campinas, SP, Brazil;1. School of Life Sciences, Devi Ahilya University, Indore, 452001 India;2. All India Institute of Medical Sciences, Patna, 801507 India;1. College of Animal Science and Veterinary Medicine, Jilin University, Changchun, China;2. College of Food Science and Engineering, Jilin University, Changchun, China |
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| Abstract: | ObjectiveStaphylococcus aureus (S. aureus), one of Gram-positive pathogen, is frequently associated with acute lung inflammation. The central feature of S. aureus acute lung inflammation are pulmonary dysfunctioning and impeded host defence response, which cause failure in inflammatory cytokines homeostasis and leads to serious tissue damage. However, the role of the Mer receptor tyrosine kinase (MerTK) in the lung following S. aureus infection remains elusive. Here, we investigate whether MerTK alleviates S. aureus induced uncontrolled inflammation through negatively regulating toll-like receptor 2 and 6 (TLR2/ TLR6) via suppressor of cytokine signalling 1, 3 (SOCS1/SOCS3).Methods and resultsWe found in mice lung tissues and RAW 264.7 macrophages upon S. aureus infection activates TLR2 and TLR6 driven mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-κB) signalling pathways, resulting in production of inflammatory cytokines including tumour necrosis factor-α (TNF-α), interleukin 1β (IL-1β), interleukin 6 (IL-6). Furthermore, S. aureus-infection groups showed a significant up-regulation of MerTK which serves as mediator of SOCS1 and SOCS3. Subsequently, through feedback mechanism SOCS1/3 degrade Mal, resulting in inhibition of downstream TLR mediated inflammatory pathways. Moreover, MerTK−/− mice lung tissues and silencing MerTK in RAW 264.7 inhibited the S. aureus-induced activation of MerTK, which significantly upregulated the phosphorylation of crucial protein in MAPKs (ERK, JNK, p38) and NF-κB (IĸBα, p65) signalling pathways, as well as the production of pro-inflammatory cytokines.ConclusionCollectively, these findings indicate the important role of MerTK in self-regulatory resolution of S. aureus-induced inflammatory pathways and cytokines through intrinsic SOCS1 and SOCS3 repressed feedback on TLR2, TLR6 both in vivo and in vitro. |
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| Keywords: | MerTK TLR Lung inflammation Immune regulation |
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