Myeloid-related protein-14 contributes to protective immunity in gram-negative pneumonia derived sepsis

PLoS Pathog. 2012;8(10):e1002987. doi: 10.1371/journal.ppat.1002987. Epub 2012 Oct 25.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / immunology
  • ATP-Binding Cassette Transporters / metabolism
  • Animals
  • Calgranulin B / genetics
  • Calgranulin B / immunology*
  • Calgranulin B / metabolism
  • Cell Line
  • Humans
  • Klebsiella Infections / immunology*
  • Klebsiella Infections / microbiology
  • Klebsiella pneumoniae / immunology*
  • Lung / immunology
  • Lung / metabolism
  • Lung / microbiology
  • Macrophages
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neutrophils / immunology*
  • Phagocytosis
  • Pneumonia, Bacterial / immunology*
  • Pneumonia, Bacterial / microbiology
  • Sepsis / immunology*
  • Sepsis / microbiology

Substances

  • ABCC11 protein, human
  • ATP-Binding Cassette Transporters
  • Calgranulin B

Grants and funding

This work is supported by a grant from the Landsteiner Foundation for Blood Transfusion Research (project LSBR 0706) and the Interdisciplinary Centre of Clinical Research, University of Münster (Vo2/014/09) to TV. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.