Journal Article

BCL6 modulates tissue neutrophil survival and exacerbates pulmonary inflammation following influenza virus infection

Ye, Zhenqing, Melnick, Ari M., Zhang, Ruixuan, Zhu, Bibo, Jiang, Li, Xiang, Min, Kita, Hirohito, Sun, Jie, Li, Chaofan, Dent, Alexander L.

2019

Overview

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 Cretransgenic, 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.

• Publisher: National Academy of Sciences
• Subject: Animals / Apoptosis / Apoptosis - physiology / Bcl-6 protein / Biological Sciences / Bone marrow / Depletion / Disease resistance / Disruption / Gene expression / Host-Pathogen Interactions - physiology / Immunology and Inflammation / Infections / Inflammation / Influenza / Influenza A / Influenza A virus - pathogenicity / Leukocytes (neutrophilic) / Lung - metabolism / Lung - virology / Lungs / Macrophages / Macrophages, Alveolar - metabolism / Macrophages, Alveolar - virology / Mice / Mice, Inbred C57BL / Mice, Knockout / Monocytes / Morbidity / Myeloid cells / Neutrophil Infiltration - physiology / Neutrophils / Neutrophils - metabolism / Neutrophils - virology / Orthomyxoviridae Infections - metabolism / Pneumonia - metabolism / Pneumonia - virology / Proto-Oncogene Proteins c-bcl-6 - metabolism / Respiratory tract / Respiratory Tract Infections - metabolism / Respiratory Tract Infections - virology / Survival / Viral infections / Viruses