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Vagus nerve controls resolution and pro-resolving mediators of inflammation.

Mirakaj V, Dalli J, Granja T, Rosenberger P, Serhan CN - J. Exp. Med. (2014)

Bottom Line: In netrin-1(+/-) mice, resolvin D1 (RvD1) was less effective in reducing neutrophil influx promoting resolution of peritonitis compared with Ntn1(+/+).Human monocytes incubated with netrin-1 produced proresolving mediators, including resolvins and lipoxins.Netrin-1 and RvD1 displayed bidirectional activation in that they stimulated each other's expression and enhanced efferocytosis.

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Affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115 Clinic of Anesthesiology and Intensive Care Medicine, University Hospital Tübingen, Eberhard-Karls University, 72076 Tübingen, Germany.

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Netrin-1 enhances endogenous pro-resolving lipid mediators. Mouse peritonitis was initiated by i.p. injection of 1 mg of zymosan A (ZyA) and i.v. with recombinant netrin-1 (1 µg), and peritoneal exudates were collected at 4 and 12 h. Lipid mediator profiles were determined by lipid mediator metabololipidomics. (A) Representative MRM chromatograms for identified lipid mediators in murine self-resolving exudates and (B) MS/MS spectra. (C) Bioactive lipid mediators and precursor/pathway marker levels in the individual exudate at the indicated intervals as determined by MRM (see Materials and methods for details). Results are mean ± SEM and are representative of two independent experiments. n = 3–5 mice per group. *, P < 0.05; **, P < 0.01; ***, P < 0.001.
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fig6: Netrin-1 enhances endogenous pro-resolving lipid mediators. Mouse peritonitis was initiated by i.p. injection of 1 mg of zymosan A (ZyA) and i.v. with recombinant netrin-1 (1 µg), and peritoneal exudates were collected at 4 and 12 h. Lipid mediator profiles were determined by lipid mediator metabololipidomics. (A) Representative MRM chromatograms for identified lipid mediators in murine self-resolving exudates and (B) MS/MS spectra. (C) Bioactive lipid mediators and precursor/pathway marker levels in the individual exudate at the indicated intervals as determined by MRM (see Materials and methods for details). Results are mean ± SEM and are representative of two independent experiments. n = 3–5 mice per group. *, P < 0.05; **, P < 0.01; ***, P < 0.001.

Mentions: Because SPM play pivotal roles activating resolution circuits (Serhan and Savill, 2005; Serhan and Petasis, 2011), to determine whether netrin-1 impacts SPM biosynthesis during inflammation–resolution, we performed LC-MS/MS–based profiling with inflammatory exudates. In these, netrin-1 increased protectin D1 (PD1) and resolvin D5 (RvD5; Fig. 6). Netrin-1 also significantly increased 15-HETE and 12-HETE from arachidonic acid as well as docosahexaenoic acid-derived lipoxygenase products (Fig. 6 C). Levels of the chemoattractant LTB4 were significantly reduced (at 4 h) in mice given netrin-1 compared with exudates from mice challenged with ZyA alone (Fig. 6 C). In contrast, at 4 h, PGD2 and PGE2 levels were significantly elevated by netrin-1, whereas at 12 h netrin-1 significantly decreased both (Fig. 6 C). To translate this to human cells, we examined whether netrin-1 has an impact on human monocyte production of lipid mediators and performed LC-MS/MS–based LM-profiling in human monocyte incubations. Netrin-1 increased the pro-resolving mediators LXA4, LXB4, RvD1, and RvE2, and decreased TNF-stimulated production of PGD2, PGE2, PGF2α, and TXB2 (Fig. S1 and Table S2).


Vagus nerve controls resolution and pro-resolving mediators of inflammation.

Mirakaj V, Dalli J, Granja T, Rosenberger P, Serhan CN - J. Exp. Med. (2014)

Netrin-1 enhances endogenous pro-resolving lipid mediators. Mouse peritonitis was initiated by i.p. injection of 1 mg of zymosan A (ZyA) and i.v. with recombinant netrin-1 (1 µg), and peritoneal exudates were collected at 4 and 12 h. Lipid mediator profiles were determined by lipid mediator metabololipidomics. (A) Representative MRM chromatograms for identified lipid mediators in murine self-resolving exudates and (B) MS/MS spectra. (C) Bioactive lipid mediators and precursor/pathway marker levels in the individual exudate at the indicated intervals as determined by MRM (see Materials and methods for details). Results are mean ± SEM and are representative of two independent experiments. n = 3–5 mice per group. *, P < 0.05; **, P < 0.01; ***, P < 0.001.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4042652&req=5

fig6: Netrin-1 enhances endogenous pro-resolving lipid mediators. Mouse peritonitis was initiated by i.p. injection of 1 mg of zymosan A (ZyA) and i.v. with recombinant netrin-1 (1 µg), and peritoneal exudates were collected at 4 and 12 h. Lipid mediator profiles were determined by lipid mediator metabololipidomics. (A) Representative MRM chromatograms for identified lipid mediators in murine self-resolving exudates and (B) MS/MS spectra. (C) Bioactive lipid mediators and precursor/pathway marker levels in the individual exudate at the indicated intervals as determined by MRM (see Materials and methods for details). Results are mean ± SEM and are representative of two independent experiments. n = 3–5 mice per group. *, P < 0.05; **, P < 0.01; ***, P < 0.001.
Mentions: Because SPM play pivotal roles activating resolution circuits (Serhan and Savill, 2005; Serhan and Petasis, 2011), to determine whether netrin-1 impacts SPM biosynthesis during inflammation–resolution, we performed LC-MS/MS–based profiling with inflammatory exudates. In these, netrin-1 increased protectin D1 (PD1) and resolvin D5 (RvD5; Fig. 6). Netrin-1 also significantly increased 15-HETE and 12-HETE from arachidonic acid as well as docosahexaenoic acid-derived lipoxygenase products (Fig. 6 C). Levels of the chemoattractant LTB4 were significantly reduced (at 4 h) in mice given netrin-1 compared with exudates from mice challenged with ZyA alone (Fig. 6 C). In contrast, at 4 h, PGD2 and PGE2 levels were significantly elevated by netrin-1, whereas at 12 h netrin-1 significantly decreased both (Fig. 6 C). To translate this to human cells, we examined whether netrin-1 has an impact on human monocyte production of lipid mediators and performed LC-MS/MS–based LM-profiling in human monocyte incubations. Netrin-1 increased the pro-resolving mediators LXA4, LXB4, RvD1, and RvE2, and decreased TNF-stimulated production of PGD2, PGE2, PGF2α, and TXB2 (Fig. S1 and Table S2).

Bottom Line: In netrin-1(+/-) mice, resolvin D1 (RvD1) was less effective in reducing neutrophil influx promoting resolution of peritonitis compared with Ntn1(+/+).Human monocytes incubated with netrin-1 produced proresolving mediators, including resolvins and lipoxins.Netrin-1 and RvD1 displayed bidirectional activation in that they stimulated each other's expression and enhanced efferocytosis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115 Clinic of Anesthesiology and Intensive Care Medicine, University Hospital Tübingen, Eberhard-Karls University, 72076 Tübingen, Germany.

Show MeSH
Related in: MedlinePlus