Abstract
Excessive activation of neutrophils results in the release of neutrophil elastase (NE), which leads to lung injury in severe pneumonia. Previously, we demonstrated a novel immune subversion mechanism involving microbial exploitation of this NE ability, which eventually promotes disruption of the pulmonary epithelial barrier. In the present study, we investigated the effect of NE on host innate immune response. THP-1-derived macrophages were stimulated with heat-killed Streptococcus pneumoniae or lipopolysaccharide in the presence or absence of NE followed by analysis of toll-like receptor (TLR) and cytokine expression. Additionally, the biological significance of NE was confirmed in an in vivo mouse intratracheal infection model. NE downregulated the gene transcription of multiple cytokines in THP-1-derived macrophages through the cleavage of TLRs and myeloid differentiation factor 2. Additionally, NE cleaved inflammatory cytokines and chemokines. In a mouse model of intratracheal pneumococcal challenge, administration of an NE inhibitor significantly increased proinflammatory cytokine levels in bronchoalveolar lavage fluid, enhanced bacterial clearance, and improved survival rates. Our work indicates that NE subverts the innate immune response and that inhibition of this enzyme may constitute a novel therapeutic option for the treatment of pneumococcal pneumonia.
Highlights
Bacterial pneumonia constitutes a leading cause of morbidity and mortality worldwide, being responsible for approximately 3.5 million deaths annually [1]
Macrophages were stimu lated with heat-killed S. pneumoniae (HK-Spn) and LPS, which are recognized by TLR2 [22] and TLR4 [23], respectively, in the presence or absence of human neutrophil elastase (hNE)
As hNE downregulated the transcription of various cytokine genes, we hypothesized that hNE inhibits toll-like receptor (TLR) signaling in the macrophages
Summary
Bacterial pneumonia constitutes a leading cause of morbidity and mortality worldwide, being responsible for approximately 3.5 million deaths annually [1]. Streptococcus pneumoniae represents the most common cause of pneumonia in all age groups. Antibiotics comprise the primary treatment of choice for pneumonia, antimicrobial resistance among S. pneumoniae. NE Subverts Immune Response has increased significantly in past decades. The total costs of pneumococcal pneumonia reach $2.5 billion per year and are predicted to increase with the growth in the aging population in the United States [2]. Basic research is essential to provide novel therapeutic targets for pneumococcal pneumonia
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