Reduced inflammation and cytokine production in NKLAM deficient mice during Streptococcus pneumoniae infection
Donald W Lawrence1, Jacki Kornbluth1,2
1Department of Pathology, Saint Louis University School of Medicine, St. Louis, MO, United States of America.
Abstract:
Streptococcus pneumoniae is a leading cause of pneumonia and a significant economic burden. Antibiotic-resistant S. pneumoniae has become more prevalent in recent years and many pneumonia cases are caused by S. pneumoniae that is resistant to at least one antibiotic. The ubiquitin ligase natural killer lytic-associated molecule (NKLAM/RNF19b) plays a role in innate immunity and studies using NKLAM-knockout (NKLAM-KO) macrophages have demonstrated that NKLAM positively affects the transcriptional activity of STAT1. Using an inhalation infection model, we found that NKLAM-KO mice had a significantly higher lung bacterial load than WT mice but had less lung inflammation. Coincidently, NKLAM-KO mice had fewer neutrophils and NK cells in their lungs. NKLAM-KO mice also expressed less iNOS in their lungs as well as less MCP-1, MIP1α, TNFα, IL-12, and IFNγ. Both neutrophils and macrophages from NKLAM-KO mice were defective in killing S. pneumoniae as compared to wild type cells (WT). The phosphorylation of STAT1 and STAT3 in NKLAM-KO lungs was lower than in WT lungs at 24 hours post-infection. NKLAM-KO mice were afforded some protection against a lethal dose of S. pneumoniae compared to WT mice. In summary, our novel data demonstrate a role for E3 ubiquitin ligase NKLAM in modulating innate immunity via the positive regulation of inflammatory cytokine expression and bactericidal activity.
Insights
The natural killer lytic-associated molecule (NKLAM) regulates innate immunity against Streptococcus pneumoniae. NKLAM deficiency in mice reduced lung inflammation and increased survival despite higher bacterial load.
Area of Science:
- Immunology
- Microbiology
- Molecular Biology
Background:
- Streptococcus pneumoniae causes pneumonia and antibiotic resistance is increasing.
- The ubiquitin ligase NKLAM (RNF19b) is involved in innate immunity.
- NKLAM influences STAT1 transcriptional activity in macrophages.
Purpose of the Study:
- To investigate the role of NKLAM in host defense against S. pneumoniae.
- To understand NKLAM's impact on immune cell function and inflammatory responses.
Main Methods:
- Inhalation infection model using NKLAM-knockout (NKLAM-KO) and wild-type (WT) mice.
- Quantification of lung bacterial load, immune cell infiltration, and cytokine expression.
- Assessment of neutrophil and macrophage bactericidal activity.
- Analysis of STAT1 and STAT3 phosphorylation.
Main Results:
- NKLAM-KO mice exhibited higher lung bacterial load but reduced inflammation compared to WT mice.
- Fewer neutrophils and NK cells, along with lower expression of iNOS, MCP-1, MIP1α, TNFα, IL-12, and IFNγ, were observed in NKLAM-KO lungs.
- Neutrophils and macrophages from NKLAM-KO mice showed impaired S. pneumoniae killing.
- STAT1 and STAT3 phosphorylation was reduced in NKLAM-KO lungs.
- NKLAM-KO mice showed increased protection against lethal S. pneumoniae infection.
Conclusions:
- E3 ubiquitin ligase NKLAM positively regulates inflammatory cytokine expression and bactericidal activity.
- NKLAM plays a crucial role in modulating innate immunity against S. pneumoniae.
- NKLAM deficiency offers partial protection against lethal pneumococcal infection.
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