TY - JOUR
T1 - BCL6 modulates tissue neutrophil survival and exacerbates pulmonary inflammation following influenza virus infection
AU - Zhu, Bibo
AU - Zhang, Ruixuan
AU - Li, Chaofan
AU - Jiang, Li
AU - Xiang, Min
AU - Ye, Zhenqing
AU - Kita, Hirohito
AU - Melnick, Ari M.
AU - Dent, Alexander L.
AU - Sun, Jie
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank staff at the National Institutes of Health (NIH) tetramer core facility for providing tetramers for this study. This study was funded by NIH Grants R01 AI112844, R01 AG047156, and R01 HL126647 to J.S., R35 CA220499 to A.M.M., R37 AI71106 to H.K., and R01 AI132771 to A.L.D.; a Mayo Clinic Kogod Aging Center Pilot Grant and the Mayo Clinic Center for Biomedical Discovery discretionary fund to J.S.; and a grant from the Chemotherapy Foundation to A.M.M.
Publisher Copyright:
© 2019 National Academy of Sciences. All rights reserved.
PY - 2019/6/11
Y1 - 2019/6/11
N2 - 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.
AB - 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.
KW - BCL6
KW - Inflammation
KW - Influenza
KW - Neutrophil
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U2 - 10.1073/pnas.1902310116
DO - 10.1073/pnas.1902310116
M3 - Article
C2 - 31138703
AN - SCOPUS:85067205854
SN - 0027-8424
VL - 116
SP - 11888
EP - 11893
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 24
ER -