Abstract
Specialized pro-resolving mediators (SPM), primarily produced in innate immune cells, exert crucial bioactions for resolving inflammation. Among various lipoxygenases (LOX), 15-LOX-1is key for SPM biosynthesis, but cellular activation principles of 15-LOX-1are unexplored. It was shown that 3-O-acetyl-11-keto-β-boswellic acid (AKBA) shifts 5-LOX regiospecificity from 5- to 12-lipoxygenation products. Here, it is demonstrated that AKBA additionally activates cellular 15-LOX-1via an allosteric site accomplishing robust SPM formation in innate immune cells, particularly in M2macrophages. Compared to ionophore, AKBA-induced LOX activation is Ca2+ - and phosphorylation-independent, with modest induction of 5-LOX products. AKBA docks into a groove between the catalytic and regulatory domains of 15-LOX-1interacting with R98; replacement of R98by alanine abolishes AKBA-induced 15-LOX product formation in HEK293cells. In zymosan-induced murine peritonitis, AKBA strikingly elevates SPM levels and promotes inflammation resolution. Together, targeted allosteric modulation of LOX activities governs SPM formation and offers new concepts for inflammation resolution pharmacotherapy.
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