TitleBCL6 modulates tissue neutrophil survival and exacerbates pulmonary inflammation following influenza virus infection.
Publication TypeJournal Article
Year of Publication2019
AuthorsZhu, Bibo, Zhang Ruixuan, Li Chaofan, Jiang Li, Xiang Min, Ye Zhenqing, Kita Hirohito, Melnick Ari M., Dent Alexander L., and Sun Jie
JournalProc Natl Acad Sci U S A
Volume116
Issue24
Pagination11888-11893
Date Published2019 06 11
ISSN1091-6490
KeywordsAnimals, Apoptosis, Host-Pathogen Interactions, Influenza A virus, Lung, Macrophages, Alveolar, Mice, Mice, Inbred C57BL, Mice, Knockout, Neutrophil Infiltration, Neutrophils, Orthomyxoviridae Infections, Pneumonia, Proto-Oncogene Proteins c-bcl-6, Respiratory Tract Infections
Abstract

<p>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.</p>

DOI10.1073/pnas.1902310116
Alternate JournalProc Natl Acad Sci U S A
PubMed ID31138703
PubMed Central IDPMC6575592
Grant ListR35 CA220499 / CA / NCI NIH HHS / United States
R01 AG047156 / AG / NIA NIH HHS / United States
R37 AI071106 / AI / NIAID NIH HHS / United States
R21 AI119612 / AI / NIAID NIH HHS / United States
R01 AI112844 / AI / NIAID NIH HHS / United States
R01 HL126647 / HL / NHLBI NIH HHS / United States
R01 AI132771 / AI / NIAID NIH HHS / United States