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- Title
Neutrophil Elastase Subverts the Immune Response by Cleaving Toll-Like Receptors and Cytokines in Pneumococcal Pneumonia.
- Authors
Domon, Hisanori; Nagai, Kosuke; Maekawa, Tomoki; Oda, Masataka; Yonezawa, Daisuke; Takeda, Wataru; Hiyoshi, Takumi; Tamura, Hikaru; Yamaguchi, Masaya; Kawabata, Shigetada; Terao, Yutaka
- 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.
- Subjects
TOLL-like receptors; LEUCOCYTE elastase; PNEUMOCOCCAL pneumonia
- Publication
Frontiers in Immunology, 2018, p1
- ISSN
1664-3224
- Publication type
Article
- DOI
10.3389/fimmu.2018.00732