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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.
Highlights
Klebsiella (K.) pneumoniae is a frequent causative pathogen in pneumonia [1,2] and the second most common cause of gramnegative sepsis [3,4]
Neutrophils are phagocytes that are well known for their capacity to engulf and kill microbial pathogens
We here provide a likely mechanism by showing that MRP8/14 plays a role in phagocytosis and that its presence is critical in both murine and human neutrophil extracellular traps (NETs) to inhibit bacterial growth
Summary
Klebsiella (K.) pneumoniae is a frequent causative pathogen in pneumonia [1,2] and the second most common cause of gramnegative sepsis [3,4]. It is of great importance to expand our understanding on host defense mechanisms that influence the outcome of Klebsiella pneumonia. Invasive infection and accompanying inflammatory mechanisms can cause tissue damage that is associated with release of endogenous ‘‘alarm’’ proteins These proteins, known as Damage Associated Molecular Patterns (DAMPs), are recognized by pattern recognition receptors and perpetuate inflammatory responses [7,8]. Among these DAMPs, the S100 proteins MRP8 (myeloid-related protein, S100A8) and MRP14 (S100A9) have gained increasing interest [9,10].
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