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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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Vagotomy delays resolution of inflammation. Mice were subjected to right-sided cervical vagotomy or sham surgery. Netrin-1 mRNA (A) or protein (B) in the indicated tissues was quantified by quantitative real-time RT-PCR or Western blot, respectively. (C) Resolution indices as defined in (Bannenberg et al., 2005). (D and E) Mice were subjected to right-side cervical vagotomy or sham surgery and then injected i.p. with zymosan (1 mg/ml). Levels of TNF, IL-1β, IL-6, KC, MIP-1α, and HMGB1 in peritoneal lavage were measured by ELISA 4 h after zymosan injection. Acetylcholine (E) and netrin-1 levels (F, left) in peritoneal fluid at the indicated time points. Netrin-1 mRNA levels (F, right) in the peritoneal exudates were assessed by quantitative real-time RT-PCR at the indicated intervals. Results represent two independent experiments and are mean ± SEM, n = 6 mice per group. *, P < 0.05; **, P < 0.01; ***, P < 0.001.
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fig1: Vagotomy delays resolution of inflammation. Mice were subjected to right-sided cervical vagotomy or sham surgery. Netrin-1 mRNA (A) or protein (B) in the indicated tissues was quantified by quantitative real-time RT-PCR or Western blot, respectively. (C) Resolution indices as defined in (Bannenberg et al., 2005). (D and E) Mice were subjected to right-side cervical vagotomy or sham surgery and then injected i.p. with zymosan (1 mg/ml). Levels of TNF, IL-1β, IL-6, KC, MIP-1α, and HMGB1 in peritoneal lavage were measured by ELISA 4 h after zymosan injection. Acetylcholine (E) and netrin-1 levels (F, left) in peritoneal fluid at the indicated time points. Netrin-1 mRNA levels (F, right) in the peritoneal exudates were assessed by quantitative real-time RT-PCR at the indicated intervals. Results represent two independent experiments and are mean ± SEM, n = 6 mice per group. *, P < 0.05; **, P < 0.01; ***, P < 0.001.

Mentions: Because vagotomy regulates the magnitude of the inflammatory response (Tracey, 2002), we assessed the impact of vagotomy on netrin-1 expression and in peritonitis. To this end, C57BL/6 mice were subjected to unilateral vagotomy (or a comparable sham surgical procedure) 7 d before initiating inflammation. Using Western blot analysis, we determined that in vagotomized mice, netrin-1 mRNA expression was significantly reduced in organs innervated by the vagus nerve, such as the lung and the peritoneum (Fig. 1), and protein expression was reduced as well. Of interest, during peritonitis, total exudate leukocyte numbers, PMN, and the marker myeloperoxidase were significantly increased in vagotomized mice following challenge compared with sham-operated mice (data not shown). Determination of the resolution indices (Bannenberg et al., 2005) in vagotomized animals demonstrated a clear delay in resolution, with an increase in the resolution interval from Ri = 24 h to Ri = 37 h (Fig. 1 C); also, proinflammatory cytokine and chemokine levels were elevated in inflammatory exudates from vagotomized mice compared with sham mice (Fig. 1 D).


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

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

Vagotomy delays resolution of inflammation. Mice were subjected to right-sided cervical vagotomy or sham surgery. Netrin-1 mRNA (A) or protein (B) in the indicated tissues was quantified by quantitative real-time RT-PCR or Western blot, respectively. (C) Resolution indices as defined in (Bannenberg et al., 2005). (D and E) Mice were subjected to right-side cervical vagotomy or sham surgery and then injected i.p. with zymosan (1 mg/ml). Levels of TNF, IL-1β, IL-6, KC, MIP-1α, and HMGB1 in peritoneal lavage were measured by ELISA 4 h after zymosan injection. Acetylcholine (E) and netrin-1 levels (F, left) in peritoneal fluid at the indicated time points. Netrin-1 mRNA levels (F, right) in the peritoneal exudates were assessed by quantitative real-time RT-PCR at the indicated intervals. Results represent two independent experiments and are mean ± SEM, n = 6 mice per group. *, P < 0.05; **, P < 0.01; ***, P < 0.001.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4042652&req=5

fig1: Vagotomy delays resolution of inflammation. Mice were subjected to right-sided cervical vagotomy or sham surgery. Netrin-1 mRNA (A) or protein (B) in the indicated tissues was quantified by quantitative real-time RT-PCR or Western blot, respectively. (C) Resolution indices as defined in (Bannenberg et al., 2005). (D and E) Mice were subjected to right-side cervical vagotomy or sham surgery and then injected i.p. with zymosan (1 mg/ml). Levels of TNF, IL-1β, IL-6, KC, MIP-1α, and HMGB1 in peritoneal lavage were measured by ELISA 4 h after zymosan injection. Acetylcholine (E) and netrin-1 levels (F, left) in peritoneal fluid at the indicated time points. Netrin-1 mRNA levels (F, right) in the peritoneal exudates were assessed by quantitative real-time RT-PCR at the indicated intervals. Results represent two independent experiments and are mean ± SEM, n = 6 mice per group. *, P < 0.05; **, P < 0.01; ***, P < 0.001.
Mentions: Because vagotomy regulates the magnitude of the inflammatory response (Tracey, 2002), we assessed the impact of vagotomy on netrin-1 expression and in peritonitis. To this end, C57BL/6 mice were subjected to unilateral vagotomy (or a comparable sham surgical procedure) 7 d before initiating inflammation. Using Western blot analysis, we determined that in vagotomized mice, netrin-1 mRNA expression was significantly reduced in organs innervated by the vagus nerve, such as the lung and the peritoneum (Fig. 1), and protein expression was reduced as well. Of interest, during peritonitis, total exudate leukocyte numbers, PMN, and the marker myeloperoxidase were significantly increased in vagotomized mice following challenge compared with sham-operated mice (data not shown). Determination of the resolution indices (Bannenberg et al., 2005) in vagotomized animals demonstrated a clear delay in resolution, with an increase in the resolution interval from Ri = 24 h to Ri = 37 h (Fig. 1 C); also, proinflammatory cytokine and chemokine levels were elevated in inflammatory exudates from vagotomized mice compared with sham mice (Fig. 1 D).

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.

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Related in: MedlinePlus