Staphylococcus aureus bacteria can be either a harmless resident of human skin, with one in four people harboring Staphylococcus aureus bacteria on their skin and mucous membranes of the upper respiratory tract, or a major pathogen wreaking havoc on our body. A Staph infection can lead to skin inflammation, lung infections, and can even lead to sepsis. The underlying mechanisms of how infectious inflammation is resolved by the host immune system are incompletely understood.

One hallmark of inflammation resolution is the activation of specialized pro-resolving mediators (SPMs) that enhance bacterial clearance and promote tissue repair. Now, a team of researchers has found that the toxin α-hemolysin (Hla) from Staphylococcus aureus increases the amount of SPM in mice, and may even have a positive effect.

The research is published in the paper, “Staphylococcus aureus-Derived α-Hemolysin Evokes Generation of Specialized Pro-resolving Mediators Promoting Inflammation Resolution,” in Cell Reports.

The pharmacist and doctoral candidate Paul Jordan prepares bacterial cultures (Staphylococcus aureus). [Jens Meyer /University of Jena]
Work led by Oliver Werz, PhD, professor at Friedrich Schiller University Jena in Germany, showed that specific immune cells are stimulated by the bacterial toxin to produce specialized messenger substances that help to reduce inflammation and to promote tissue healing. Werz expects this hitherto unknown mechanism to be significant for future treatments of skin inflammation and chronic wounds.

Immune cells produce anti-inflammatory messenger substances

The team studied the bacterial toxin α-Hemolysin and examined its effect on M2 macrophages. M2 macrophages are immune cells which, in the later stages of an inflammatory reaction, ensure that bacteria that have been killed, and damaged cell components, are removed, and that the tissue regenerates. “They are therefore a kind of cellular waste disposal,” said Paul Jordan, pharmacist and doctoral candidate in Werz’s team and lead author of the publication, describing the function of these cells.

The researchers showed that α-hemolysin binds to specific receptor proteins on the surface of M2 macrophages and thus triggers the production of anti-inflammatory messenger substances in the cells, which then causes the inflammation to resolve.

They went on to show that the toxin does this “through selective activation of host 15-lipoxygenase-1 (15-LOX-1).” The authors wrote that “S. aureus-induced SPM formation in M2 is abolished upon Hla depletion or 15-LOX-1 knockdown” and that “isolated Hla elicits SPM formation in M2 that is reverted by inhibition of the Hla receptor ADAM10.”

In the study, the scientists were also able to show that these transmitters promote tissue regeneration in an animal model. They wrote that “lipid mediators derived from Hla-treated M2 accelerate planarian tissue regeneration.” The anti-inflammatory messenger substances include resolvins, maresins, and protectins that are formed from omega-3 fatty acids.

Graphical abstract Jordan et al.

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