Allosteric Activation of 15-Lipoxygenase-1 by Boswellic Acid Induces the Lipid Mediator Class Switch to Promote Resolution of Inflammation.
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| Abstract |
Specialized pro-resolving mediators (SPM), primarily produced in innate immune cells, exert crucial bioactions for resolving inflammation. Among various lipoxygenases (LOX), 15-LOX-1 is key for SPM biosynthesis, but cellular activation principles of 15-LOX-1 are 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-1 via an allosteric site accomplishing robust SPM formation in innate immune cells, particularly in M2 macrophages. 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-1 interacting with R98; replacement of R98 by alanine abolishes AKBA-induced 15-LOX product formation in HEK293 cells. 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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| Authors | Friedemann Börner, Simona Pace, Paul M Jordan, Jana Gerstmeier, Mario Gomez, Antonietta Rossi, Nathaniel C Gilbert, Marcia E Newcomer, Oliver Werz |
| Journal | Advanced science (Weinheim, Baden-Wurttemberg, Germany) (Adv Sci (Weinh)) Vol. 10 Issue 6 Pg. e2205604 (02 2023) ISSN: 2198-3844 [Electronic] Germany |
| PMID | 36567268 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
| Copyright | © 2022 The Authors. Advanced Science published by Wiley-VCH GmbH. |
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