The p53-Target Gene Puma Drives Neutrophil-Mediated Protection against Lethal Bacterial Sepsis
نویسندگان
چکیده
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.
منابع مشابه
Phospholipase D2 drives mortality in sepsis by inhibiting neutrophil extracellular trap formation and down-regulating CXCR2
We determined the function of phospholipase D2 (PLD2) in host defense in highly lethal mouse models of sepsis using PLD2(-/-) mice and a PLD2-specific inhibitor. PLD2 deficiency not only increases survival but also decreases vital organ damage during experimental sepsis. Production of several inflammatory cytokines (TNF, IL-1β, IL-17, and IL-23) and the chemokine CXCL1, as well as cellular apop...
متن کاملWip1 Deficiency Promotes Neutrophil Recruitment to the Infection Site and Improves Sepsis Outcome
Sepsis is defined as an uncontrolled host response to infection, and no specific therapy or drugs have been used in clinical trials currently. Discovering new therapeutic targets for sepsis treatment has always been a central problem in the field of sepsis research. Neutrophils stand at the first line in controlling infection and have been identified to be dysregulated with impaired migration a...
متن کاملImmune Protection against Lethal Fungal-Bacterial Intra-Abdominal Infections
Polymicrobial intra-abdominal infections (IAIs) are clinically prevalent and cause significant morbidity and mortality, especially those involving fungi. Our laboratory developed a mouse model of IAI and demonstrated that intraperitoneal inoculation with Candida albicans or other virulent non-albicans Candida (NAC) species plus Staphylococcus aureus resulted in 70 to 80% mortality in 48 to 72 h...
متن کاملPUMA regulates intestinal progenitor cell radiosensitivity and gastrointestinal syndrome.
Radiation is one of the most effective cancer treatments. However, gastrointestinal (GI) syndrome is a major limiting factor in abdominal and pelvic radiotherapy. The loss of crypt stem cells or villus endothelial cells has been suggested to be responsible for radiation-induced intestinal damage. We report here a critical role of the BH3-only protein p53 upregulated modulator of apoptosis (PUMA...
متن کاملInhibition of IL-10 Production by Maternal Antibodies against Group B Streptococcus GAPDH Confers Immunity to Offspring by Favoring Neutrophil Recruitment
Group B Streptococcus (GBS) is the leading cause of neonatal pneumonia, septicemia, and meningitis. We have previously shown that in adult mice GBS glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is an extracellular virulence factor that induces production of the immunosuppressive cytokine interleukin-10 (IL-10) by the host early upon bacterial infection. Here, we investigate...
متن کامل