Abstract 415: Resolvin D1 Limits 5-lipoxygenase Nuclear Localization and Leukotriene B4 Synthesis by Inhibiting a Calcium-activated Kinase Pathway
Introduction: Imbalances between pro-inflammatory and pro-resolving mediators can lead to chronic inflammatory diseases, such as atherosclerosis. Hypothesis: The balance of arachidonic acid (AA)-derived mediators in leukocytes is thought to be achieved through intracellular localization of 5-lipoxygenase (5-LOX): nuclear 5-LOX favors the biosynthesis of pro-inflammatory leukotriene B4 (LTB4), while, in theory, cytoplasmic 5-LOX could favor the biosynthesis of pro-resolving lipoxin A4 (LXA4). This balance is shifted in favor of LXA4 by resolvin D1 (RvD1), a specialized pro-resolving mediator (SPM) derived from docosahexaenoic acid (DHA), but the mechanism is not known. Hence we hypothesized that RvD1 regulates 5-LOX localization in macrophages.
Methods/Results: Here we report a new pathway through which RvD1 promotes nuclear exclusion of 5-LOX and thereby suppresses LTB4 and enhances LXA4 in macrophages. RvD1, by activating its receptor FPR2/ALX, suppresses cytosolic calcium and decreases activation of the calcium-sensitive kinase CaMKII. CaMKII inhibition suppresses activation P38 and MAPKAPK2 kinases, which reduces Ser271 phosphorylation of 5-LOX and shifts 5-LOX from the nucleus to the cytoplasm. As such, RvD1’s ability to decrease nuclear 5-LOX and the LTB4:LXA4 ratio in vitro and in vivo was mimicked by macrophages lacking CaMKII or expressing S271A-5-LOX. Importantly, nuclear localization of 5-LOX has been reported in unstable advanced human atherosclerotic lesions, hence strategies to reverse this process are of interest. In this regard, RvD1 treatment of Ldlr-/- mice reduced macrophage 5-LOX localization and stabilized advanced plaques.
Conclusions: Knowledge of this mechanism may provide new strategies for promoting inflammation resolution in chronic inflammatory diseases, like atherosclerosis.
Author Disclosures: G. Fredman: None.
- © 2015 by American Heart Association, Inc.