Lipoxin A4 attenuates endothelial dysfunction during experimental cerebral malaria

Abstract A breakdown of the brain–blood barrier (BBB) due to endothelial dysfunction is a primary feature of cerebral malaria (CM). Lipoxins (LX) are specialized pro-resolving mediators that attenuate endothelial dysfunction in different vascular beds. It has already been shown that LXA 4 prolonged Plasmodium berghei -infected mice survival by a mechanism that depends on inhibiting IL-12 production and CD8 + IFN-γ + T cells in brain tissue; however, the effects of this treatment on endothelial dysfunction induced during experimental cerebral malaria (ECM) remains to be elucidated. Herein, we investigate the role of LXA 4 on endothelial dysfunction during ECM. The treatment of P. berghei -infected mice with LXA 4 prevented BBB breakdown and ameliorated behavioral symptoms but did not modulate TNF-α production. In addition, microcirculation analysis showed that treatment with LXA 4 significantly increased functional capillary density in brains of P. berghei -infected C57BL/6 mice. Furthermore, histological analyses of brain sections demonstrated that exogenous LXA 4 reduced capillary congestion that was accompanied by reduced ICAM-1 expression in the brain tissue. In agreement, LXA 4 treatment of endothelial cells stimulated by Plasmodium berghei ( Pb )- or Plasmodium falciparum ( Pf )-parasitized red blood cells (RBCs) inhibited ICAM-1 expression. Additionally, LXA 4 treatment restored the expression of HO-1 that is reduced during ECM. As well, LXA 4 treatment inhibits Pb RBC and Pf RBC adhesion to endothelial cells that was reversed by the use of an HO-1 inhibitor (ZnPPIX). Our results demonstrate for the first time that LXA 4 ameliorates endothelial dysfunction during ECM by modulating ICAM-1 and HO-1 expression in brain tissue.