title: The p53-target gene puma drives neutrophil-mediated protection against lethal bacterial sepsis.
abstract: 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.
authors.affiliation: Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors.forename: Sean P
authors.initials: SP
authors.lastname: Garrison
authors.forename: Justin A
authors.initials: JA
authors.lastname: Thornton
authors.forename: Hans
authors.initials: H
authors.lastname: Häcker
authors.forename: Richard
authors.initials: R
authors.lastname: Webby
authors.forename: Jerold E
authors.initials: JE
authors.lastname: Rehg
authors.forename: Evan
authors.initials: E
authors.lastname: Parganas
authors.forename: Gerard P
authors.initials: GP
authors.lastname: Zambetti
authors.forename: Elaine I
authors.initials: EI
authors.lastname: Tuomanen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D001424:Bacterial Infections / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D016158:Genes, p53; D007113:Immunity, Innate; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology*; D018805:Sepsis / Q000276:immunology*; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*
chemical_list: D051017:Apoptosis Regulatory Proteins; C488588:PUMA protein, mouse; D025521:Tumor Suppressor Proteins