Neutrophils recruited by leukotriene B4 induce features of plaque destabilization during endotoxemia.

Aims: Both leukotrienes and neutrophils have been linked to plaque destabilization. Despite being evoked, the role of leukotriene B4 on neutrophil recruitment to plaques and the concomitant effects of these two actors on plaque stability remain to be proven. Since both actors are elicited during endotoxemia, a condition associated with the risk of cardiovascular events, we investigated whether endotoxemia promotes leukotriene B4-mediated neutrophil infiltration in plaques and explored the roles of leukotriene B4 and neutrophils in plaque destabilization.

Methods and Results: Endotoxemia induced by repeated peritoneal endotoxin injections at a non-lethal dose (1.5 mg/kg, 5 days) in chow-fed aged Apoe-/- mice (over 45 week-old) resulted in neutrophil infiltration and activation in plaques. Subsequently to neutrophil invasion, plaques exhibited increased features of vulnerability: reduced collagen content, expanded necrotic cores, and thinned fibrous caps. These plaque features were reproduced by direct deposition of isolated neutrophils onto murine atheromatous carotid arteries in an in vivo assay. In endotoxemic mice, plaques produced increased amounts of leukotriene B4. Genomic or pharmacological impairments of this production reduced neutrophil infiltration, collagenolysis, and apoptosis of smooth muscle cells in plaques of endotoxemic mice. Furthermore, conditioned media of human culprit plaques contained more leukotriene B4 than non-culprit plaques and levels of leukotriene B4 correlated to both neutrophil activation markers and endotoxin releases in culprit plaques.

Conclusions: These results show that the increased neutrophil recruitment elicited by leukotriene B4 contributes to increase features of plaque destabilization in endotoxemic contexts, and point out leukotriene B4 as a potential therapeutic target in atherosclerosis.