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Published on: February 28, 2019
Interleukin-1 receptor-associated kinase M-deficient mice demonstrate an improved host defense during Gram-negative
Jacobien J Hoogerwerf1, Gerritje J W van der Windt, Dana C Blok
1Center for Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
Abstract:
Pneumonia is a common cause of morbidity and mortality and the most frequent source of sepsis. Bacteria that try to invade normally sterile body sites are recognized by innate immune cells through pattern recognition receptors, among which toll-like receptors (TLRs) feature prominently. Interleukin-1 receptor (IL-1R)-associated kinase (IRAK)-M is a proximal inhibitor of TLR signaling expressed by epithelial cells and macrophages in the lung. To determine the role of IRAK-M in host defense against bacterial pneumonia, IRAK-M-deficient (IRAK-M(-/-)) and normal wild-type (WT) mice were infected intranasally with Klebsiella pneumoniae. IRAK-M mRNA was upregulated in lungs of WT mice with Klebsiella pneumonia, and the absence of IRAK-M resulted in a strongly improved host defense as reflected by reduced bacterial growth in the lungs, diminished dissemination to distant body sites, less peripheral tissue injury and better survival rates. Although IRAK-M(-/-) alveolar macrophages displayed enhanced responsiveness toward intact K. pneumoniae and Klebsiella lipopolysaccharide (LPS) in vitro, IRAK-M(-/-) mice did not show increased cytokine or chemokine levels in their lungs after infection in vivo. The extent of lung inflammation was increased in IRAK-M(-/-) mice shortly after K. pneumoniae infection, as determined by semiquantitative scoring of specific components of the inflammatory response in lung tissue slides. These data indicate that IRAK-M impairs host defense during pneumonia caused by a common gram-negative respiratory pathogen.
Insights
Interleukin-1 receptor (IL-1R)-associated kinase (IRAK)-M impairs host defense against Klebsiella pneumoniae pneumonia. Eliminating IRAK-M in mice improved bacterial clearance, reduced tissue damage, and increased survival rates.
Area of Science:
- Immunology
- Infectious Diseases
- Pulmonology
Background:
- Pneumonia is a leading cause of death and sepsis, often caused by bacterial pathogens.
- Innate immunity, particularly toll-like receptor (TLR) signaling, is crucial for combating bacterial invasion.
- Interleukin-1 receptor (IL-1R)-associated kinase (IRAK)-M is an inhibitor of TLR signaling found in lung epithelial cells and macrophages.
Purpose of the Study:
- To investigate the role of IRAK-M in the host defense against bacterial pneumonia.
- To determine the impact of IRAK-M deficiency on the response to Klebsiella pneumoniae infection.
Main Methods:
- Comparison of wild-type (WT) and IRAK-M-deficient (IRAK-M(-/-)) mice infected intranasally with Klebsiella pneumoniae.
- Assessment of bacterial load, dissemination, tissue injury, survival rates, and inflammatory markers in the lungs.
- In vitro analysis of macrophage responsiveness to K. pneumoniae and lipopolysaccharide (LPS).
Main Results:
- IRAK-M mRNA was upregulated in WT mice during Klebsiella pneumonia.
- IRAK-M(-/-) mice exhibited reduced bacterial growth, less dissemination, diminished tissue injury, and improved survival.
- IRAK-M(-/-) alveolar macrophages showed enhanced in vitro responsiveness, but in vivo cytokine/chemokine levels were not increased.
- Lung inflammation was elevated in IRAK-M(-/-) mice early post-infection.
Conclusions:
- IRAK-M plays a detrimental role in host defense against Klebsiella pneumoniae pneumonia.
- IRAK-M deficiency enhances bacterial clearance and survival, despite increased early inflammation.
- Targeting IRAK-M may represent a therapeutic strategy for bacterial pneumonia.
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