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

Abstract

Lipoxin A 4 (LXA 4 ) is an endogenous lipid mediator that requires transcellular metabolic traffic for its synthesis. The targets of LXA 4 on neutrophils are well described, contributing to attenuation of inflammation. However, effects of lipoxins on macrophage are less known, particularly the action of LXA 4 on the regulation of apoptosis of these cells. Our data show that pretreatment of human or murine macrophages with LXA 4 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/IFNc challenge. The release of mitochondrial mediators of apoptosis and the activation of caspases was abrogated in the presence of LXA 4 . 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 LXA 4 identified an early activation of the PI3K/Akt and ERK/Nrf-2 pathways, which was required for the observation of the antiapoptotic effects of LXA 4 . 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.

Modulation of Voltage-Dependent and Inward Rectifier Potassium Channels by 15-Epi-Lipoxin-A4 in Activated Murine Macrophages: Implications in Innate Immunity

“…1B). In agreement with previous data (22) and in part due to the attenuation of the LPS-dependent activation, treatment of BMDM with e-LXA 4 protected against apoptosis (Fig. 1C).…”

“…1E). In agreement with this anti-inflammatory pattern (22), a decrease in the expression of NOS-2 and COX-2 and a moderate expression of HO-1 (an Nrf2-dependent gene) at 10 h after e-LXA 4 /LPS challenge was observed (Fig. 1F).…”

“…Lipoxins are endogenous eicosanoids released during the resolution phase of inflammation (17)(18)(19)(20)(21), and they might modulate K v activity. The potent anti-inflammatory and proresolving actions of these lipids have been demonstrated in multiple animal models of human diseases (22,23). Both native LXA 4 and e-LXA 4 (20) bind to and activate the ALX receptor and decrease polymorphonuclear cells infiltration in rodent models of acute peritonitis (24).…”

Targeting resolution of neuroinflammation after ischemic stroke with a lipoxin A4 analog: Protective mechanisms and long‐term effects on neurological recovery

“…This indicates that BML‐111 increases CD163 + cells through a different mechanism than IL‐4 or IL‐10 stimulation, such as direct stimulation on the cells and bypassing cytokine stimulation entirely. This possibility is supported by the fact that both microglia and macrophages express the receptor ALX, and previous studies have shown direct effects of LXA 4 on macrophages to promote debris clearance, inhibit apoptosis, and activate pro‐resolution pathways (Godson et al., 2000; Prieto et al., 2010). Much of what we know of the phenotypes of microglia and macrophages are from in vitro experiments, which do not accurately convey the complexity of an in vivo system, especially one with injury.…”

Lipoxin A4 activates alveolar epithelial sodium channel gamma via the microRNA-21/PTEN/AKT pathway in lipopolysaccharide-induced inflammatory lung injury

“…51 In contrast, Prieto et al found that pretreatment with LXA 4 promoted a rapid activation of ERK after staurosporine challenge in RAW 264.7 cells. 52 These differences were probably a consequence of signaling convergence and cross-talk between the AKT and ERK cascades.…”