Neutrophils recruited by leukotriene B₄ induce features of plaque destabilization during endotoxaemia

Both leukotrienes and neutrophils have been linked to plaque destabilization. Despite being evoked, the role of leukotriene B₄ (LTB₄) in 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 endotoxaemia, a condition associated with the risk of cardiovascular events, we investigated whether endotoxaemia promotes LTB₄-mediated neutrophil infiltration in plaques and explored the roles of LTB₄ and neutrophils in plaque destabilization.

Endotoxaemia 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 weeks 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 LTB₄. 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 (CPs) contained more LTB₄ than non-CPs and levels of LTB₄ correlated to both neutrophil activation markers and endotoxin releases in CPs.

These results show that the increased neutrophil recruitment elicited by LTB₄ contributes to increase features of plaque destabilization in endotoxemic contexts and point out LTB₄ as a potential therapeutic target in atherosclerosis.