Lipoxin A₄ impairment of apoptotic signaling in macrophages: Implication of the PI3K/Akt and the ERK/Nrf-2 defense pathways

Lipoxin A₄ (LXA₄) is an endogenous lipid mediator that requires transcellular metabolic traffic for its synthesis. The targets of LXA₄ on neutrophils are well described, contributing to attenuation of inflammation. However, effects of lipoxins on macrophage are less known, particularly the action of LXA₄ on the regulation of apoptosis of these cells. Our data show that pretreatment of human or murine macrophages with LXA₄ at the concentrations prevailing in the course of resolution of inflammation (nanomolar range) significantly inhibits the apoptosis induced by staurosporine, etoposide and S-nitrosoglutathione or by more pathophysiological stimuli, such as LPS/IFNγ challenge. The release of mitochondrial mediators of apoptosis and the activation of caspases was abrogated in the presence of LXA₄. In addition to this, the synthesis of reactive oxygen species induced by staurosporine was attenuated and antiapoptotic proteins of the Bcl-2 family accumulated in the presence of lipoxin. Analysis of the targets of LXA₄ identified an early activation of the PI3K/Akt and ERK/Nrf-2 pathways, which was required for the observation of the antiapoptotic effects of LXA₄. These data suggest that the LXA ₄, released after the recruitment of neutrophils to sites of inflammation, exerts a protective effect on macrophage viability that might contribute to a better resolution of inflammation.