Resolvin E1 promotes phagocytosis-induced neutrophil apoptosis and accelerates resolution of pulmonary inflammation

Abstract

Inappropriate neutrophil activation contributes to the pathogenesis of acute lung injury (ALI). Apoptosis is essential for removal of neutrophils from inflamed tissues and timely resolution of inflammation. Resolvin E1 (RvE1) is an endogenous lipid mediator derived from the ω-3 polyunsaturated fatty acid eicosapentaenoic acid that displays proresolving actions. Because the balance of prosurvival and proapoptosis signals determines the fate of neutrophils, we investigated the impact of RvE1 on neutrophil apoptosis and the outcome of neutrophil-mediated pulmonary inflammation in mice. Culture of human neutrophils with RvE1 accelerated apoptosis evoked by phagocytosis of opsonized Escherichia coli or yeast. RvE1 through the leukotriene B 4 receptor BLT1 enhanced NADPH oxidase-derived reactive oxygen species generation and subsequent activation of caspase-8 and caspase-3. RvE1 also attenuated ERK and Akt-mediated apoptosis-suppressing signals from myeloperoxidase, serum amyloid A, and bacterial DNA, shifting the balance of pro-and anti-survival signals toward apoptosis via induction of mitochondrial dysfunction. In mice, RvE1 treatment enhanced the resolution of established neutrophil-mediated pulmonary injury evoked by intratracheal instillation or i.p. administration of live E. coli or intratracheal instillation of carrageenan plus myeloperoxidase via facilitating neutrophil apoptosis and their removal by macrophages. The actions of RvE1 were prevented by the pancaspase inhibitor zVAD-fmk. These results identify a mechanism, promotion of phagocytosis-induced neutrophil apoptosis and mitigation of potent anti-apoptosis signals, by which RvE1 could enhance resolution of acute lung inflammation.leukocytes | efferocytosis | innate immunity | resolution of inflammation

Dietary -3 fatty acids protect against vasculopathy in a transgenic mouse model of sickle cell disease

“…This is in agreement with recent studies on the protective role of ω-3-derived pro-resolving mediators in models of acute lung injury. 57,58 The proresolving effects of FD supplementation during H/R stress were also evident in aortas of SS-FD mice, in which we observed a marked reduction in H/R-induced HO-1 expression and prevention of the H/R-induced expression of antioxidant systems such as SOD-1 and Prx2 ( Figure 6A). …”

Efferocytosis and Lung Disease

“…51 Resolvin E1 enhances apoptosis and uptake of human neutrophils induced by microbe ingestion and reduced lung infl ammation in three murine models. 52 Conversely, instillation of apoptotic cells into the lungs of mice following bleomycin lung injury reduced infl ammatory cytokine production and lung fi brosis via hepatocyte growth factor-dependent mechanisms, resulting in increased survival. 53 This last fi nding suggests that autologous apoptotic cell therapy might be benefi cial in selected settings, if issues of timing and dosage could be defi ned.…”

Biasing the lipoxin A 4 /formyl peptide receptor 2 pushes inflammatory resolution

“…It is noteworthy that LXA 4 and resolvin E1 counterregulated the leukotriene B 4 (LTB 4 )/LL-37 proinflammatory circuit, which is mediated by the LTB 4 receptor BLT1 and ALX (8). Resolvin E1 can activate a proresolution circuit through BLT1 (17), highlighting the complex interplay between these lipid mediators and their receptors. Despite these fascinating findings, many intriguing questions about ALX remain.…”