TNF-mediated alveolar macrophage necroptosis drives disease pathogenesis during respiratory syncytial virus infection
| Autor: | Leonardo Duarte Santos, Fábio Luiz Dal Moro Maito, Ana Paula de Souza, Jaqueline de Souza Felipe, Ricardo Weinlich, Gabriela de Souza, Rafael S. Czepielewski, Karen Magnus, Amanda Gonzalez da Silva, Bárbara N. Porto, Stéfanie Primon Muraro, Marco Aurélio Ramirez Vinolo, Marcelo Comerlato Scotta, Rita Mattiello, Larissa C. Zanetti, Krist Helen Antunes |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Pulmonary and Respiratory Medicine Programmed cell death viruses Necroptosis Respiratory Syncytial Virus Infections Lung injury Mice 03 medical and health sciences 0302 clinical medicine Macrophages Alveolar medicine Animals Macrophage Infection and Basic Science Lung business.industry Original Articles respiratory system 030104 developmental biology medicine.anatomical_structure Respiratory Syncytial Virus Human 030220 oncology & carcinogenesis Immunology Alveolar macrophage Bronchiolitis Respiratory virus Tumor necrosis factor alpha business |
| Zdroj: | The European Respiratory Journal article-version (VoR) Version of Record |
| ISSN: | 1399-3003 0903-1936 |
| DOI: | 10.1183/13993003.03764-2020 |
| Popis: | Respiratory syncytial virus (RSV) is the major cause of acute bronchiolitis in infants under 2 years old. Necroptosis has been implicated in the outcomes of respiratory virus infections. We report that RSV infection triggers necroptosis in primary mouse macrophages and human monocytes in a RIPK1-, RIPK3- and MLKL-dependent manner. Moreover, necroptosis pathways are harmful to RSV clearance from alveolar macrophages. Additionally, Ripk3−/− mice were protected from RSV-induced weight loss and presented with reduced viral loads in the lungs. Alveolar macrophage depletion also protected mice from weight loss and decreased lung RSV virus load. Importantly, alveolar macrophage depletion abolished the upregulation of Ripk3 and Mlkl gene expression induced by RSV infection in the lung tissue. Autocrine tumor necrosis factor (TNF)-mediated RSV-triggered macrophage necroptosis and necroptosis pathways were also involved in TNF secretion even when macrophages were committed to cell death, which can worsen lung injury during RSV infection. In line, Tnfr1−/− mice had a marked decrease in Ripk3 and Mlkl gene expression and a sharp reduction in the numbers of necrotic alveolar macrophages in the lungs. Finally, we provide evidence that elevated nasal levels of TNF are associated with disease severity in infants with RSV bronchiolitis. We propose that targeting TNF and/or the necroptotic machinery may be valuable therapeutic approaches to reduce the respiratory morbidity caused by RSV infection in young children. RIPK1-, RIPK3- and MLKL-dependent alveolar macrophage necroptosis triggered by RSV infection is mediated by autocrine TNF and harmful to viral clearance. Alveolar macrophage necroptosis may drive RSV disease pathogenesis. https://bit.ly/3fS34uw |
| Databáze: | OpenAIRE |
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