Decursinol Angelate Mitigates Sepsis Induced by Methicillin-Resistant Staphylococcus aureus Infection by Modulating the Inflammatory Responses of Macrophages

Abstract

The herbal plant Angelica gigas (A. gigas) has been used in traditional medicine in East Asian countries, and its chemical components are reported to have many pharmacological effects. In this study, we showed that a bioactive ingredient of A. gigas modulates the functional activity of macrophages and investigated its effect on inflammation using a sepsis model. Among 12 different compounds derived from A. gigas, decursinol angelate (DA) was identified as the most effective in suppressing the induction of TNF-α and IL-6 in murine macrophages. When mice were infected with a lethal dose of methicillin-resistant Staphylococcus aureus (MRSA), DA treatment improved the mortality and bacteremia, and attenuated the cytokine storm, which was associated with decreased CD38+ macrophage populations in the blood and liver. In vitro studies revealed that DA inhibited the functional activation of macrophages in the expression of pro-inflammatory mediators in response to microbial infection, while promoting the bacterial killing ability with an increased production of reactive oxygen species. Mechanistically, DA treatment attenuated the NF-κB and Akt signaling pathways. Intriguingly, ectopic expression of an active mutant of IKK2 released the inhibition of TNF-α production by the DA treatment, whereas the inhibition of Akt resulted in enhanced ROS production. Taken together, our experimental evidence demonstrated that DA modulates the functional activities of pro-inflammatory macrophages and that DA could be a potential therapeutic agent in the management of sepsis.

Oleuropein Mitigates Lipopolysaccharide-Induced Alveolar Epithelial Cell Oxidative Stress and Apoptosis by Regulating lncRNA Gm4419 Expression

“…Natural plants or their active ingredients have shown great advantages and potential in sepsis treatment due to multiple targets of action, multiple routes of administration, and fewer side effects [29,30] . OLEU has a variety of pharmacological activities.…”

ADAM10-a “multitasker” in sepsis: focus on its posttranslational target

“…ADAM10 knockdown produced the same result. In response to methicillin-resistant Staphylococcus aureus (MRSA) infection, macrophages have also been reported to functionally activate the expression of proinflammatory mediators in vitro, induce a cytokine storm in vivo, and increase mortality and bacteremia [ 94 ]. In addition to harming the host, α-toxin can activate specialized pro-resolving mediators (SPMs) in human M2-like macrophages to promote the resolution of infectious inflammation, which can be reversed by inhibition of the α-toxin receptor ADAM10 [ 95 ].…”