Trappin-2 Promotes Early Clearance of Pseudomonas aeruginosa through CD14-Dependent Macrophage Activation and Neutrophil Recruitment

Abstract

Microaspiration of Pseudomonas aeruginosa contributes to the pathogenesis of nosocomial pneumonia. Trappin-2 is a host defense peptide that assists with the clearance of P. aeruginosa through undefined mechanisms. A model of macrophage interactions with replicating P. aeruginosa (strain PA01) in serum-free conditions was developed, and the influence of subantimicrobial concentrations of trappin-2 was subsequently studied. PA01 that was pre-incubated with trappin-2 (at concentrations that have no direct antimicrobial effects), but not control PA01, was cleared by alveolar and bone marrow-derived macrophages. However, trappin-2-enhanced clearance of PA01 was completely abrogated by CD14- null macrophages. Fluorescence microscopy demonstrated the presence of trappin-2 on the bacterial cell surface of trappin-2-treated PA01. In a murine model of early lung infection, trappin-2-treated PA01 was cleared more efficiently than control PA01 2 hours of intratracheal instillation. Furthermore, trappin-2-treated PA01 up-regulated the murine chemokine CXCL1/KC after 2 hours with a corresponding increase in neutrophil recruitment 1 hour later. These in vivo trappin-2-treated PA01 effects were absent in CD14-deficient mice. Trappin-2 appears to opsonize P. aeruginosa for more efficient, CD14-dependent clearance by macrophages and contributes to the induction of chemokines that promote neutrophil recruitment. Trappin-2 may therefore play an important role in innate recognition and clearance of pathogens during the very earliest stages of pulmonary infection.

Anti-HIV-1 Activity of Elafin Is More Potent than Its Precursor's, Trappin-2, in Genital Epithelial Cells

“…To date, there are no published reports that utilized the knockdown approach to assess the role of Tr/E in antimicrobial and especially antiviral defense mechanisms. However, the fact that rodents, who are naturally devoid of Tr/E, show increased susceptibility to Staphylococcus aureus infection and higher microbial load in lungs compared to their Tr/E-expressing counterparts (42) could relate to our findings (4,70,80). Furthermore, elevated levels of Tr/E found in CVLs of HIV-R CSWs would also imply a negative relationship between Tr/E and viral susceptibility/clearance.…”

Innate Immune Responses to Systemic Acinetobacter baumannii Infection in Mice: Neutrophils, but Not Interleukin-17, Mediate Host Resistance

“…IL-17 is known to be responsible for induction of downstream chemokines, such as KC/CXCL1, which are chemotactic for neutrophils (58). The induction of KC/ CXCL1 following infection has been documented for a wide variety of pathogens, including bacterial infections such as Pseudomonas aeruginosa (45,51,56), Chlamydia muridarum (63), Citrobacter rodentium (50,55), Listeria monocytogenes (53), Streptococcus pneumoniae (48,54), Leptospira interrogans (8), and Borrelia burgdorferi (3). In the present studies, KC/ CXCL1 induction was evaluated following systemic A. baumannii infection in C3HeB/FeJ mice.…”

The Compromise of Macrophage Functions by Hyperoxia Is Attenuated by Ethacrynic Acid via Inhibition of NF-κB–Mediated Release of High-Mobility Group Box-1

“…Bone marrow cells were harvested from 8-to 12-week-old female C57BL/6 mice and cultured as described previously (35,36). Briefly, femurs were removed, cleaned, and placed into tubes containing sterile PBS.…”