Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
PLoS Pathog. 2010 Dec 23;6(12):e1001240. doi: 10.1371/journal.ppat.1001240.
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.
p53/Puma 介导的细胞凋亡的破坏可防止因 DNA 损伤而导致的致死性。在这里，我们证明了促凋亡 p53 靶基因 Puma 在对细菌性败血症产生成功的固有免疫反应中的意外需求。当受到细菌挑战时，Puma⁻/⁻小鼠迅速死亡。虽然 Puma⁻/⁻小鼠的免疫反应在细胞迁移、吞噬作用和细菌杀伤方面没有改变，但感染部位积聚了大的脓肿，败血症呈进行性发展。在感染过程中阻断 p53/Puma 诱导的细胞凋亡会导致 CD49d+中性粒细胞亚群对 ROS 诱导的细胞死亡产生抗性，从而导致免疫反应不足。这项研究确定了 p53/Puma 凋亡在优化中性粒细胞寿命方面的生物学作用，以确保适当清除细菌，并揭示了感染固有免疫反应与 DNA 损伤后生存之间的平衡。
