Toll-Like Receptor 4 Agonistic Antibody Promotes Host Defense against Chronic Pseudomonas aeruginosa Lung Infection in Mice
Autor: | Yoshitsugu Miyazaki, Hiroshi Mukae, Koichi Izumikawa, Kenji Fukudome, Kazuhiro Oshima, Katsunori Yanagihara, Naoki Iwanaga, Shigeru Kohno, Masafumi Seki, Taiga Miyazaki, Shigeki Nakamura |
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Rok vydání: | 2016 |
Předmět: |
CD4-Positive T-Lymphocytes
0301 basic medicine Neutrophils Phagocytosis Immunology Microbiology Mice 03 medical and health sciences 0302 clinical medicine Immune system Pseudomonas infection Pneumonia Bacterial medicine Animals Mice Knockout Toll-like receptor Microbial Viability Innate immune system biology Antibodies Monoclonal Opsonin Proteins medicine.disease Bacterial Load Immunity Innate Toll-Like Receptor 4 Disease Models Animal 030104 developmental biology Infectious Diseases Neutrophil elastase Microbial Immunity and Vaccines Chronic Disease Pseudomonas aeruginosa biology.protein TLR4 Cytokines Female Parasitology Serine Proteases Antibody 030215 immunology |
Zdroj: | Infection and Immunity. 84:1986-1993 |
ISSN: | 1098-5522 0019-9567 |
Popis: | Chronic lower respiratory tract infection with Pseudomonas aeruginosa is difficult to treat due to enhanced antibiotic resistance and decreased efficacy of drug delivery to destroyed lung tissue. To determine the potential for restorative immunomodulation therapies, we evaluated the effect of Toll-like receptor 4 (TLR4) stimulation on the host immune response to Pseudomonas infection in mice. We implanted sterile plastic tubes precoated with P. aeruginosa in the bronchi of mice, administered the TLR4/MD2 agonistic monoclonal antibody UT12 intraperitoneally every week, and subsequently analyzed the numbers of viable bacteria and inflammatory cells and the levels of cytokines. We also performed flow cytometry-based phagocytosis and opsonophagocytic killing assays in vitro using UT12-treated murine peritoneal neutrophils. UT12-treated mice showed significantly enhanced bacterial clearance, increased numbers of Ly6G + neutrophils, and increased concentrations of macrophage inflammatory protein 2 (MIP-2) in the lungs ( P < 0.05). Depletion of CD4 + T cells eliminated the ability of the UT12 treatment to improve bacterial clearance and promote neutrophil recruitment and MIP-2 production. Additionally, UT12-pretreated peritoneal neutrophils exhibited increased opsonophagocytic killing activity via activation of the serine protease pathway, specifically neutrophil elastase activity, in a TLR4-dependent manner. These data indicated that UT12 administration significantly augmented the innate immune response against chronic bacterial infection, in part by promoting neutrophil recruitment and bactericidal function. |
Databáze: | OpenAIRE |
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