title: PAD4-deficiency does not affect bacteremia in polymicrobial sepsis and ameliorates endotoxemic shock.
abstract: Neutrophil extracellular traps (NETs), consisting of nuclear DNA with histones and microbicidal proteins, are expelled from activated neutrophils during sepsis. NETs were shown to trap microbes, but they also fuel cardiovascular, thrombotic, and autoimmune disease. The role of NETs in sepsis, particularly the balance between their antimicrobial and cytotoxic actions, remains unclear. Neutrophils from peptidylarginine deiminase 4-(PAD4(-/-)) deficient mice, which lack the enzyme allowing for chromatin decondensation and NET formation, were evaluated. We found that neutrophil functions involved in bacterial killing, other than NETosis, remained intact. Therefore, we hypothesized that prevention of NET formation might not have devastating consequences in sepsis. To test this, we subjected the PAD4(-/-) mice to mild and severe polymicrobial sepsis produced by cecal ligation and puncture. Surprisingly, under septic conditions, PAD4(-/-) mice did not fare worse than wild-type mice and had comparable survival. In the presence of antibiotics, PAD4-deficiency resulted in slightly accelerated mortality but bacteremia was unaffected. PAD4(-/-) mice were partially protected from lipopolysaccharide-induced shock, suggesting that PAD4/NETs may contribute to the toxic inflammatory and procoagulant host response to endotoxin. We propose that preventing NET formation by PAD4 inhibition in inflammatory or thrombotic diseases is not likely to increase host vulnerability to bacterial infections.
authors.affiliation: Immunology Graduate Program, Division of Medical Sciences, Harvard Medical School, Boston, MA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA; Department of Pediatrics, Harvard Medical School, Boston, MA;
authors.forename: Kimberly
authors.initials: K
authors.lastname: Martinod
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA; Department of Pediatrics, Harvard Medical School, Boston, MA;
authors.forename: Tobias A
authors.initials: TA
authors.lastname: Fuchs
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA; Department of Pediatrics, Harvard Medical School, Boston, MA; Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, Boston, MA;
authors.forename: Naamah L
authors.initials: NL
authors.lastname: Zitomersky
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA; Department of Pediatrics, Harvard Medical School, Boston, MA;
authors.forename: Siu Ling
authors.initials: SL
authors.lastname: Wong
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA; Department of Pediatrics, Harvard Medical School, Boston, MA;
authors.forename: Melanie
authors.initials: M
authors.lastname: Demers
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA;
authors.forename: Maureen
authors.initials: M
authors.lastname: Gallant
authors.affiliation: Center for Eukaryotic Gene Regulation, Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA; and.
authors.forename: Yanming
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA; Department of Pediatrics, Harvard Medical School, Boston, MA; Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA.
authors.forename: Denisa D
authors.initials: DD
authors.lastname: Wagner
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D016470:Bacteremia / Q000276:immunology; D003433:Crosses, Genetic; D019446:Endotoxemia / Q000382:microbiology*; D005434:Flow Cytometry; D006657:Histones / Q000378:metabolism; D006867:Hydrolases / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation; D008070:Lipopolysaccharides / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018375:Neutrophil Activation / Q000276:immunology; D009504:Neutrophils / Q000378:metabolism; D010538:Peritonitis / Q000382:microbiology; D000080002:Protein-Arginine Deiminase Type 4; D018805:Sepsis / Q000382:microbiology*
chemical_list: D000900:Anti-Bacterial Agents; D006657:Histones; D008070:Lipopolysaccharides; D006867:Hydrolases; D000080002:Protein-Arginine Deiminase Type 4; C552151:peptidylarginine deiminase 4, mouse