Btk inhibitor ibrutinib reduces inflammatory myeloid cell responses in the lung during murine pneumococcal pneumonia

Background Streptococcus pneumoniae is a major causative agent in community-acquired pneumonia and sepsis. Overwhelming lung inflammation during pneumococcal pneumonia may hamper lung function. Ibrutinib is an irreversible inhibitor of Bruton’s tyrosine kinase (Btk), a key signaling protein controll...

Full description

Saved in:
Bibliographic Details
Published in:Molecular medicine (Cambridge, Mass.) Vol. 25; no. 1; pp. 3 - 10
Main Authors: de Porto, Alexander P., Liu, Zhe, de Beer, Regina, Florquin, Sandrine, de Boer, Onno J., Hendriks, Rudi W., van der Poll, Tom, de Vos, Alex F.
Format: Journal Article
Language:English
Published: London BioMed Central 15.01.2019
Springer Nature B.V
BMC
Subjects:
Agammaglobulinaemia Tyrosine Kinase - antagonists & inhibitors
Animals
Anti-Bacterial Agents - therapeutic use
Anti-Inflammatory Agents - therapeutic use
Biomedical and Life Sciences
Biomedicine
Bronchoalveolar Lavage Fluid - cytology
Bruton’s tyrosine kinase
Ceftriaxone - therapeutic use
Cytokines
Experiments
Flow cytometry
Ibrutinib
Inflammation
Inhibitor drugs
Kinases
Lavage
Lipopolysaccharides
Lung - drug effects
Lung - immunology
Male
Mice, Inbred C57BL
Mice, Knockout
Molecular Medicine
Myeloid Cells - drug effects
Myeloid Cells - immunology
Pneumonia
Pneumonia, Pneumococcal - drug therapy
Pneumonia, Pneumococcal - immunology
Protein Kinase Inhibitors - therapeutic use
Pyrazoles - therapeutic use
Pyrimidines - therapeutic use
Research Article
Sepsis
Statistical analysis
Streptococcus infections
Streptococcus pneumoniae
Teichoic Acids
Tumor necrosis factor-TNF
Netherlands
Bruton’s tyrosine kinase
Sepsis
Pneumonia
Ibrutinib
Streptococcus pneumoniae
ISSN:1076-1551, 1528-3658, 1528-3658
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Background Streptococcus pneumoniae is a major causative agent in community-acquired pneumonia and sepsis. Overwhelming lung inflammation during pneumococcal pneumonia may hamper lung function. Ibrutinib is an irreversible inhibitor of Bruton’s tyrosine kinase (Btk), a key signaling protein controlling the activation of various immune cells, including macrophages and neutrophils. The aim of this study was to determine whether ibrutinib treatment ameliorates acute lung inflammation during pneumococcal pneumonia. Methods Mice were treated orally with ibrutinib and the effect on acute pulmonary inflammation elicited by the gram-positive bacterial cell wall component lipoteichoic acid (LTA) and during ceftriaxone-treated pneumococcal pneumonia was assessed. Results Treatment with ibrutinib prior to and after intranasal LTA instillation reduced alveolar macrophage activation, neutrophil influx, cytokine release and plasma leakage into the lung. Postponed treatment with ibrutinib supplementing antibiotic therapy during ongoing pneumococcal pneumonia did not impair bacterial killing in lung, blood and spleen. In this setting, ibrutinib reduced alveolar macrophage and systemic neutrophil activation and substantially diminished further monocyte and neutrophil influx in the lung. In vitro, ibrutinib inhibited macrophage TNF secretion and neutrophil activation upon LTA and pneumococcal stimulation. Conclusions Taken together, these data indicate that the Btk inhibitor ibrutinib reduces inflammatory myeloid cell responses during acute pulmonary inflammation evoked by LTA and antibiotic-treated pneumococcal pneumonia and suggest that ibrutinib has the potential to inhibit ongoing lung inflammation in an acute infectious setting.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 14
content type line 23
ISSN:1076-1551
1528-3658
1528-3658
DOI:10.1186/s10020-018-0069-7