Neutrophil Elastase Subverts the Immune Response by Cleaving Toll-Like Receptors and Cytokines in Pneumococcal Pneumonia

Frontiers in Immunology

Masataka Oda¹  Masaya Yamaguchi²  Shigetada Kawabata²  Kosuke Nagai³  Daisuke Yonezawa⁴  Hikaru Tamura⁵  Takumi Hiyoshi⁵  Tomoki Maekawa⁵  Wataru Takeda⁶  Hisanori Domon⁷  Yutaka Terao⁷ 

[1] Department of Microbiology and Infection Control Sciences, Kyoto Pharmaceutical University, Kyoto, Japan;Department of Oral and Molecular Microbiology, Osaka University, Graduate School of Dentistry, Osaka, Japan;Division of Microbiology and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan;Division of Oral Science for Health Promotion, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan;Division of Periodontology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan;Faculty of Dentistry, Niigata University, Niigata, Japan;Research Center for Advanced Oral Science, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan;

关键词: neutrophil elastase;    pneumonia;    innate immune response;    toll-like receptor;    Streptococcus pneumoniae;    cytokines;   

DOI  :  10.3389/fimmu.2018.00732

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown