Article ; Online: BCL6 modulates tissue neutrophil survival and exacerbates pulmonary inflammation following influenza virus infection.
Proceedings of the National Academy of Sciences of the United States of America
2019 Volume 116, Issue 24, Page(s) 11888–11893
Abstract: ... indicate that tissue-specific regulation of neutrophil survival modulates host inflammation and tissue ... and morbidity following IAV infection. Mechanistically, BCL6 bound to the neutrophil gene loci ... neutrophil depletion led to diminished pulmonary inflammation and decreased host morbidity. Our results ...
| Abstract | Neutrophils are vital for antimicrobial defense; however, their role during viral infection is less clear. Furthermore, the molecular regulation of neutrophil fate and function at the viral infected sites is largely elusive. Here we report that BCL6 deficiency in myeloid cells exhibited drastically enhanced host resistance to severe influenza A virus (IAV) infection. In contrast to the notion that BCL6 functions to suppress innate inflammation, we find that myeloid BCL6 deficiency diminished lung inflammation without affecting viral loads. Using a series of Cre-transgenic, reporter, and knockout mouse lines, we demonstrate that BCL6 deficiency in neutrophils, but not in monocytes or lung macrophages, attenuated host inflammation and morbidity following IAV infection. Mechanistically, BCL6 bound to the neutrophil gene loci involved in cellular apoptosis in cells specifically at the site of infection. As such, BCL6 disruption resulted in increased expression of apoptotic genes in neutrophils in the respiratory tract, but not in the circulation or bone marrow. Consequently, BCL6 deficiency promoted tissue neutrophil apoptosis. Partial neutrophil depletion led to diminished pulmonary inflammation and decreased host morbidity. Our results reveal a previously unappreciated role of BCL6 in modulating neutrophil apoptosis at the site of infection for the regulation of host disease development following viral infection. Furthermore, our studies indicate that tissue-specific regulation of neutrophil survival modulates host inflammation and tissue immunopathology during acute respiratory viral infection. |
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| MeSH term(s) | Animals ; Apoptosis/physiology ; Host-Pathogen Interactions/physiology ; Influenza A virus/pathogenicity ; Lung/metabolism ; Lung/virology ; Macrophages, Alveolar/metabolism ; Macrophages, Alveolar/virology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neutrophil Infiltration/physiology ; Neutrophils/metabolism ; Neutrophils/virology ; Orthomyxoviridae Infections/metabolism ; Pneumonia/metabolism ; Pneumonia/virology ; Proto-Oncogene Proteins c-bcl-6/metabolism ; Respiratory Tract Infections/metabolism ; Respiratory Tract Infections/virology | |||||
| Chemical Substances | Bcl6 protein, mouse ; Proto-Oncogene Proteins c-bcl-6 | |||||
| Keywords | covid19 | |||||
| Language | English | |||||
| Publishing date | 2019-05-28 | |||||
| Publishing country | United States | |||||
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't | |||||
| ZDB-ID | 209104-5 | |||||
| ISSN | 1091-6490 ; 0027-8424 | |||||
| ISSN (online) | 1091-6490 | |||||
| ISSN | 0027-8424 | |||||
| DOI | 10.1073/pnas.1902310116 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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