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.
