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Targeted p38 mitogen-activated protein kinase inhibition potently augment inflammatory responses of human macrophages
Astrid Lund1, David Moffat2, Stine Dam Jepsen1
1Laboratory of Immunology, Section for Preclinical Disease Biology, Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
Abstract:
Antibiotic-resistant Staphylococcus aureus (S. aureus) is a growing challenge for human health and novel treatment options are needed. Here we examine a novel therapeutic approach against persistent S. aureus infections based on monocyte/macrophage specific inhibition of the p38α mitogen-activated protein kinase activity. Since systemic p38α kinase inhibition cause aberrant toxicity, we used the myeloid specific p38α kinase inhibitor, MPL-5821. P38α kinase inhibition caused a potent increase in the pro-inflammatory profile of human macrophages after exposure to S. aureus, including upregulation of M1-markers and induction of pro-inflammatory cytokines including IFN-γ, TNF-α, IL-1β, IL12p70, IL-6 and IL-8, as well as an increase in phagocytic capacities. These pro-inflammatory signals were only seen after combined S. aureus exposure and p38α inhibition. Macrophages are often regulated by changes in intracellular metabolism. In agreement with this, the combination of S. aureus exposure and p38α inhibition led to specific changes in glycolytic and mitochondrial activity within the responding macrophages. Our study thus unravels a novel and specific activation of macrophages that augment their response toward S. aureus, without causing aberrant inflammation. This constitutes a unique non-antibiotic therapeutic approach that can potentially be used against persistent S. aureus infection.
Insights
This study explores a novel non-antibiotic therapy for persistent Staphylococcus aureus infections. Targeting p38α kinase in macrophages enhances their ability to fight S. aureus without causing harmful inflammation.
Area of Science:
- Immunology
- Pharmacology
- Microbiology
Background:
- Antibiotic-resistant Staphylococcus aureus poses a significant threat to human health, necessitating new therapeutic strategies.
- Current treatments face challenges due to rising resistance and the need for novel approaches against persistent infections.
Purpose of the Study:
- To investigate a novel therapeutic strategy for persistent Staphylococcus aureus infections using myeloid-specific inhibition of p38α mitogen-activated protein kinase.
- To evaluate the effects of p38α kinase inhibition on macrophage pro-inflammatory responses and phagocytic activity in the context of S. aureus infection.
Main Methods:
- Utilized the myeloid-specific p38α kinase inhibitor, MPL-5821, in combination with S. aureus exposure.
- Assessed changes in macrophage pro-inflammatory markers (M1-markers, cytokines like IFN-γ, TNF-α, IL-1β, IL12p70, IL-6, IL-8), phagocytic capacity, and intracellular metabolism (glycolytic and mitochondrial activity).
Main Results:
- p38α kinase inhibition significantly enhanced the pro-inflammatory profile of human macrophages upon S. aureus exposure.
- Observed upregulation of M1-markers and induction of key pro-inflammatory cytokines, alongside increased phagocytic capacities.
- Demonstrated specific alterations in macrophage glycolytic and mitochondrial activity when treated with the combined S. aureus and p38α inhibition approach.
Conclusions:
- The combined approach of S. aureus exposure and myeloid-specific p38α inhibition activates macrophages effectively against S. aureus without inducing aberrant inflammation.
- This represents a promising non-antibiotic therapeutic avenue for combating persistent S. aureus infections.
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