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

Research Center, Maisonneuve-Rosemont Hospital, and Department of Pathology and Cell Biology, University of Montréal, Montréal, QC, Canada H1T 2M4.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 08/2012; 109(37):14983-8. DOI: 10.1073/pnas.1206641109
Source: PubMed


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 pan-caspase 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.

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    • "Apop PMN (El Kebir et al. 2009) Escherichia coli (El Kebir et al. 2009) Multimicrobial sepsis/CLP (Walker et al. 2011) Apop PMN (Godson et al. 2000; Schwab et al. 2007) Serum-treated zymosan (Schwab et al. 2007) Latex beads (Schwab et al. 2007) E. coli (Prescott and McKay 2011) RvE1 STZ (Schwab et al. 2007) HSV-1 (Rajasagi et al. 2011) E. coli (Seki et al. 2010; El Kebir et al. 2012) Candida albicans (Haas-Stapleton et al. 2007) Apop PMN (Schwab et al. 2007; Oh et al. 2011) Serum-treated zymosan (Schwab et al. 2007; Ohira et al. 2010; Oh et al. 2011) Latex beads (Schwab et al. 2007) E. coli (Oh et al. 2011) 18S-RvE1 Apop PMN (Oh et al. 2011) Serum-treated zymosan (Oh et al. 2011) E. coli (Oh et al. 2011) RvE2 Serum-treated zymosan (Oh et al. 2011) PD1 STZ (Schwab et al. 2007) Apop PMN (El Kebir et al. 2009) E. coli (Chiang et al. 2012) E. coli (Chiang et al. 2012) Serum-treated zymosan (Schwab et al. 2007) Apop PMN (Schwab et al. 2007) Latex beads (Schwab et al. 2007) E. coli (Chiang et al. 2012) RvD1 E. coli (Chiang et al. 2012) Apop PMN (Hsiao et al. 2013) E. coli (Chiang et al. 2012) Serum-treated zymosan (Krishnamoorthy et al. 2010) Apop PMN (Krishnamoorthy et al. 2010) E. coli (Chiang et al. 2012) AT-RvD1 E. coli (Palmer et al. 2011) IgG-OVA-coated beads (Rogerio et al. 2012) RvD2 Multimicrobial sepsis/CLP (Spite et al. 2009) E. coli (Spite et al. 2009) Serum-treated zymosan (Spite et al. 2009) RvD3 AT-RvD3 "
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    • "ALI is characterized by excessive neutrophil infiltration, release of proinflammatory mediators, and loss of vascular barrier integrity [19]. During airway inflammation, neutrophils are the first cells to be recruited and are the predominant cause of tissue damage [20]. "
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    • "Survival signals, such as GM-CSF, preserve Mcl-1 expression predominantly through inhibition of its proteasomal degradation [31]. Importantly, therapeutic strategies to induce neutrophil apoptosis with cyclin-dependent kinase inhibitors [32], aspirin-triggered 15-epi-lipoxin A4 [33], annexin A1 [34] and resolvin E1 [35] appear to be mediated through modulation of Mcl-1 expression. Suppression of apoptosis in neutrophils in whole blood by TLR agonists, including CpG DNA was found to coincide with higher intracellular Mcl-1 levels [21], however, whether this could be attributed to a direct action of CpG DNA on neutrophils as well as the underlying molecular mechanisms have not been elucidated. "
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