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

PLoS Pathogens

Marieke A. D. van Zoelen¹  Ahmed Achouiti¹  Johannes Roth¹  Thomas Vogl²  Cornelis van 't Veer²  Sandrine Florquin²  Tijmen J. Hommes³  Marc Röhm³  Alex F. de Vos⁴  Constantin F. Urban⁵  Tom van der Poll⁵ 

[1] Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;Center for Infection and Immunity, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;Clinical Microbiology Department, Laboratory for Molecular Infection Medicine Sweden, Umeå University, Umeå, Sweden;Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;Institute of Immunology, University of Münster, Münster, Germany

关键词: Klebsiella pneumoniae;    Neutrophils;    Klebsiella infections;    Klebsiella pneumonia;    Sepsis;    Cytokines;    Macrophages;    Pneumonia;   

DOI  :  10.1371/journal.ppat.1002987

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY