title: Myeloid-related protein-14 contributes to protective immunity in gram-negative pneumonia derived sepsis.
abstract: Klebsiella (K.) pneumoniae is a common cause of pneumonia-derived sepsis. Myeloid related protein 8 (MRP8, S100A8) and MRP14 (S100A9) are the most abundant cytoplasmic proteins in neutrophils. They can form MRP8/14 heterodimers that are released upon cell stress stimuli. MRP8/14 reportedly exerts antimicrobial activity, but in acute fulminant sepsis models MRP8/14 has been found to contribute to organ damage and death. We here determined the role of MRP8/14 in K. pneumoniae sepsis originating from the lungs, using an established model characterized by gradual growth of bacteria with subsequent dissemination. Infection resulted in gradually increasing MRP8/14 levels in lungs and plasma. Mrp14 deficient (mrp14(-/-)) mice, unable to form MRP8/14 heterodimers, showed enhanced bacterial dissemination accompanied by increased organ damage and a reduced survival. Mrp14(-/-) macrophages were reduced in their capacity to phagocytose Klebsiella. In addition, recombinant MRP8/14 heterodimers, but not MRP8 or MRP14 alone, prevented growth of Klebsiella in vitro through chelation of divalent cations. Neutrophil extracellular traps (NETs) prepared from wildtype but not from mrp14(-/-) neutrophils inhibited Klebsiella growth; in accordance, the capacity of human NETs to kill Klebsiella was strongly impaired by an anti-MRP14 antibody or the addition of zinc. These results identify MRP8/14 as key player in protective innate immunity during Klebsiella pneumonia.
authors.affiliation: Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. a.achouiti@amc.nl
authors.forename: Ahmed
authors.initials: A
authors.lastname: Achouiti
authors.forename: Thomas
authors.initials: T
authors.lastname: Vogl
authors.forename: Constantin F
authors.initials: CF
authors.lastname: Urban
authors.forename: Marc
authors.initials: M
authors.lastname: Röhm
authors.forename: Tijmen J
authors.initials: TJ
authors.lastname: Hommes
authors.forename: Marieke A D
authors.initials: MA
authors.lastname: van Zoelen
authors.forename: Sandrine
authors.initials: S
authors.lastname: Florquin
authors.forename: Johannes
authors.initials: J
authors.lastname: Roth
authors.forename: Cornelis
authors.initials: C
authors.lastname: van 't Veer
authors.forename: Alex F
authors.initials: AF
authors.lastname: de Vos
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000276:immunology / Q000378:metabolism; D000818:Animals; D040502:Calgranulin B / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D007710:Klebsiella Infections / Q000276:immunology* / Q000382:microbiology; D007711:Klebsiella pneumoniae / Q000276:immunology*; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008264:Macrophages; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology*; D010587:Phagocytosis; D018410:Pneumonia, Bacterial / Q000276:immunology* / Q000382:microbiology; D018805:Sepsis / Q000276:immunology* / Q000382:microbiology
chemical_list: C435500:ABCC11 protein, human; D018528:ATP-Binding Cassette Transporters; D040502:Calgranulin B