Elucidation of the mechanisms underlying agonist-induced lipid mediator biosynthesis in macrophages and mast cells

Infections with antibiotic-resistant S. aureus strains are one of the most common serious bacterial infections worldwide. The acute inflammatory response and its subsequent resolution are central processes to overcoming bacterial invaders and returning to homeostasis. Unresolved inflammation and hyperinflammatory events worsen the disease outcome and are strongly connected to chronicity and mortality. The underlying mechanisms of how infectious inflammation is initiated and how the inflammatory responses can become a hyperactivated life-threatening status are incompletely understood. This thesis aims at providing new mechanistic insights into the inflammation process and resolution mechanisms upon bacterial infection of different innate immune cells to further translate into therapeutic strategies for human diseases. We focused on macrophages and mast cells and their unique LM profiles after exposure to bacterial virulence factors or endogenously released patterns. Major aims are the evaluation of pharmacological modulation of LM networks and the elucidation of potent activators of 15-LOX-1 to underline the role of 15-LOX-1 and SPMs in promoting resolution of inflammation in bacterial infections. Also, the ability to manipulate macrophages polarization during S. aureus infections and mechanisms, which lead to hyperinflammation caused by endogenous derived DAMPs, are addressed. Furthermore, we aimed at studying the beneficial effects of SPMs during bacterial infections in order to encourage a rethinking and improvement of commonly used therapeutic treatments.