The p53-Target Gene Puma Drives Neutrophil-Mediated Protection against Lethal Bacterial Sepsis

PLoS Pathogens

Evan Parganas¹  Sean P. Garrison¹  Gerard P. Zambetti¹  Richard Webby²  Hans Häcker²  Justin A. Thornton²  Elaine I. Tuomanen²  Jerold E. Rehg³ 

[1] Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America;Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America;Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America

关键词: Neutrophils;    Apoptosis;    Pneumococcus;    Sepsis;    Macrophages;    White blood cells;    Flow cytometry;    Bone marrow cells;   

DOI  :  10.1371/journal.ppat.1001240

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Disruption of p53/Puma-mediated apoptosis protects against lethality due to DNA damage. Here we demonstrate the unexpected requirement of the pro-apoptotic p53-target gene Puma to mount a successful innate immune response to bacterial sepsis. Puma−/− mice rapidly died when challenged with bacteria. While the immune response in Puma−/− mice was unchanged in cell migration, phagocytosis and bacterial killing, sites of infection accumulated large abscesses and sepsis was progressive. Blocking p53/Puma-induced apoptosis during infection caused resistance to ROS-induced cell death in the CD49d+ neutrophil subpopulation, resulting in insufficient immune resolution. This study identifies a biological role for p53/Puma apoptosis in optimizing neutrophil lifespan so as to ensure the proper clearance of bacteria and exposes a counter-balance between the innate immune response to infection and survival from DNA damage.

【 授权许可】

CC BY