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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    • "RvE1 also exerts potent anti-inflammatory actions via the regulation of cytokine production in experimental models of colitis (Arita et al., 2005) and peritonitis (Schwab et al., 2007). RvE1 increases neutrophil apoptosis, enhances phagocytosis by macrophages (enhanced bacterial clearance) and decreases levels of pro-inflammatory cytokines (El Kebir et al., 2012;Seki et al., 2010). "

    Full-text · Article · Jan 2016
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    • "This inhibition reduces the adhesion of neutrophils to endothelial cells and decreases the levels of inflammatory cytokines produced by activated neu- trophils[6]. Additionally, 3-PUFAs suppress the phosphorylation of extracellular signal regulated protein kinases 1 and 2 (ERK1/2) and c-Jun N-terminal kinases 1 and 2 (JNK1/2) in macrophages[7,8], while 3-PUFA-derived resolvin E1 promotes the clearance of apoptotic neutrophils in inflammatory tissues and reduces the expression of inflammatory cytokines and chemokines[9]. Lp-PLA 2 , also known as platelet-activating factor acetylhydrolase (PAFAH), hydrolyzes platelet activating factor (PAF) or related oxidized phospholipids to eliminate inflammatory complexity in vitro and in rodent models[10,11]. "
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    ABSTRACT: Scopeω3-polyunsaturated fatty acids (ω3-PUFAs) have beneficial effects on cardiovascular function, and lipoprotein-associated phospholipase A2 (Lp-PLA2) is associated with the risk of cardiovascular disease. Here, we investigated the effects of ω3-PUFAs on Lp-PLA2 expression in vitro and in vivo and explored the mechanisms involved.Methods and resultsHuman monocytic cells (THP-1) were induced into macrophages in an in vitro model. ω3-PUFAs suppressed Lp-PLA2 expression; the suppression induced by docosahexaenoic acid (DHA) was related to reduced inflammation. Tumor necrosis factor-α (TNF-α) was employed to stimulate the phosphorylation of p38 mitogen-activated protein kinase (MAPK), nuclear factor-κB (NF-κB) p65 and Lp-PLA2 expression in macrophages. The stimulation were inhibited by DHA and the anti-inflammatory drug sodium salicylate. Moreover, the stimulation of Lp-PLA2 expression by TNF-α could be suppressed by NF-κB and MAPK pathway inhibitors. Then, chronic inflammation was induced in an in vivo mouse model, resulting in an increase in Lp-PLA2 expression in peripheral blood mononuclear cells (PBMCs) and arteries. This increase was suppressed by ω3-PUFAs. Inhibition of Lp-PLA2 transcription in PBMCs was also observed in ω3-PUFA-enriched swine.Conclusion Our results demonstrate that the protective effects of ω3-PUFAs against cardiovascular events may be related to the suppression of Lp-PLA2 levels.This article is protected by copyright. All rights reserved
    Full-text · Article · May 2015 · Molecular Nutrition & Food Research
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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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    ABSTRACT: Mounting of the acute inflammatory response is crucial for host defense and pivotal to the development of chronic inflammation, fibrosis, or abscess formation versus the protective response and the need of the host tissues to return to homeostasis. Within self-limited acute inflammatory exudates, novel families of lipid mediators are identified, named resolvins (Rv), protectins, and maresins, which actively stimulate cardinal signs of resolution, namely, cessation of leukocytic infiltration, counterregulation of proinflammatory mediators, and the uptake of apoptotic neutrophils and cellular debris. The biosynthesis of these resolution-phase mediators in sensu stricto is initiated during lipid-mediator class switching, in which the classic initiators of acute inflammation, prostaglandins and leukotrienes (LTs), switch to produce specialized proresolving mediators (SPMs). In this work, we review recent evidence on the structure and functional roles of these novel lipid mediators of resolution. Together, these show that leukocyte trafficking and temporal spatial signals govern the resolution of self-limited inflammation and stimulate homeostasis.
    Full-text · Article · Oct 2014 · Cold Spring Harbor perspectives in biology
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