Myeloid-Related Protein-14 Contributes to Protective Immunity in Gram-Negative Pneumonia Derived Sepsis

<div><p><em>Klebsiella (K.) pneumoniae</em> 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 <em>K. pneumoniae</em> 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. <em>Mrp14</em> deficient <em>(mrp14^−/−)</em> mice, unable to form MRP8/14 heterodimers, showed enhanced bacterial dissemination accompanied by increased organ damage and a reduced survival. <em>Mrp14^−/−</em> macrophages were reduced in their capacity to phagocytose <em>Klebsiella</em>. In addition, recombinant MRP8/14 heterodimers, but not MRP8 or MRP14 alone, prevented growth of <em>Klebsiella in vitro</em> through chelation of divalent cations. Neutrophil extracellular traps (NETs) prepared from wildtype but not from <em>mrp14^−/−</em> neutrophils inhibited <em>Klebsiella</em> growth; in accordance, the capacity of human NETs to kill <em>Klebsiella</em> 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 <em>Klebsiella</em> pneumonia.</p>