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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 stimulates resolution via RvD1. Resolution indices were used as previously defined (Bannenberg et al., 2005), including Ψmax (maximal PMN), Tmax (time point when PMNs reach Ψmax), T50 (time point corresponding to 50% reduction), and Ri (resolution interval, the time interval from Ψmax to 50% reduction point [i.e., T50-Tmax]). (A) Mice were injected i.p. with 1 mg of zymosan A (ZyA) and, subsequently, i.v. with either vehicle or recombinant netrin-1 (1 µg). Peritoneal exudates were collected at indicated time intervals and neutrophils (PMN) were enumerated by using light microscopy and flow cytometry. (B) Mice were treated as in panel A, and netrin-1 was given at the peak of inflammation (4h after ZyA). (C) Ntn1+/+ were injected i.p. with ZyA (1 mg) and subsequently with RvD1 (1 µg/mouse). Recruited leukocytes were enumerated at indicated time points. (D) Ntn1+/+ and Ntn1+/− mice were injected i.p. with ZyA (1mg) and subsequently with vehicle or RvD1 (1 µg/mouse), and peritoneal exudates were collected at indicated time intervals. Results in A–D represent 2 independent experiments with n = 4–6 mice per treatment per time point expressed as mean.
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fig4: Netrin-1 stimulates resolution via RvD1. Resolution indices were used as previously defined (Bannenberg et al., 2005), including Ψmax (maximal PMN), Tmax (time point when PMNs reach Ψmax), T50 (time point corresponding to 50% reduction), and Ri (resolution interval, the time interval from Ψmax to 50% reduction point [i.e., T50-Tmax]). (A) Mice were injected i.p. with 1 mg of zymosan A (ZyA) and, subsequently, i.v. with either vehicle or recombinant netrin-1 (1 µg). Peritoneal exudates were collected at indicated time intervals and neutrophils (PMN) were enumerated by using light microscopy and flow cytometry. (B) Mice were treated as in panel A, and netrin-1 was given at the peak of inflammation (4h after ZyA). (C) Ntn1+/+ were injected i.p. with ZyA (1 mg) and subsequently with RvD1 (1 µg/mouse). Recruited leukocytes were enumerated at indicated time points. (D) Ntn1+/+ and Ntn1+/− mice were injected i.p. with ZyA (1mg) and subsequently with vehicle or RvD1 (1 µg/mouse), and peritoneal exudates were collected at indicated time intervals. Results in A–D represent 2 independent experiments with n = 4–6 mice per treatment per time point expressed as mean.

Mentions: Because vagotomy reduced RvD1 levels, we tested whether RvD1 could rescue the hyperinflammatory response obtained with vagotomy. Indeed, results in Fig. 3 indicate that administration of RvD1 rescued the excessive increased PMN infiltration that resulted from vagotomy (caused by vagus nerve cutting). RvD1 stopped PMN influx in the vagotomized animals and regulated the exudate monocyte recruitment (Fig. 3 A). In these exudates, RvD1 also reduced TNF, IL-6, KC (IL-8 in humans), MIP-1α, and HMGB-1 (Fig. 3 B). Also, netrin-1 reduced Ri when given at either T0 (Fig. 4 A) or at the maximum PMN infiltration (Fig. 4 B). In both cases, netrin-1 shortened the time required to resolve inflammation.


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 stimulates resolution via RvD1. Resolution indices were used as previously defined (Bannenberg et al., 2005), including Ψmax (maximal PMN), Tmax (time point when PMNs reach Ψmax), T50 (time point corresponding to 50% reduction), and Ri (resolution interval, the time interval from Ψmax to 50% reduction point [i.e., T50-Tmax]). (A) Mice were injected i.p. with 1 mg of zymosan A (ZyA) and, subsequently, i.v. with either vehicle or recombinant netrin-1 (1 µg). Peritoneal exudates were collected at indicated time intervals and neutrophils (PMN) were enumerated by using light microscopy and flow cytometry. (B) Mice were treated as in panel A, and netrin-1 was given at the peak of inflammation (4h after ZyA). (C) Ntn1+/+ were injected i.p. with ZyA (1 mg) and subsequently with RvD1 (1 µg/mouse). Recruited leukocytes were enumerated at indicated time points. (D) Ntn1+/+ and Ntn1+/− mice were injected i.p. with ZyA (1mg) and subsequently with vehicle or RvD1 (1 µg/mouse), and peritoneal exudates were collected at indicated time intervals. Results in A–D represent 2 independent experiments with n = 4–6 mice per treatment per time point expressed as mean.
© Copyright Policy - openaccess
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fig4: Netrin-1 stimulates resolution via RvD1. Resolution indices were used as previously defined (Bannenberg et al., 2005), including Ψmax (maximal PMN), Tmax (time point when PMNs reach Ψmax), T50 (time point corresponding to 50% reduction), and Ri (resolution interval, the time interval from Ψmax to 50% reduction point [i.e., T50-Tmax]). (A) Mice were injected i.p. with 1 mg of zymosan A (ZyA) and, subsequently, i.v. with either vehicle or recombinant netrin-1 (1 µg). Peritoneal exudates were collected at indicated time intervals and neutrophils (PMN) were enumerated by using light microscopy and flow cytometry. (B) Mice were treated as in panel A, and netrin-1 was given at the peak of inflammation (4h after ZyA). (C) Ntn1+/+ were injected i.p. with ZyA (1 mg) and subsequently with RvD1 (1 µg/mouse). Recruited leukocytes were enumerated at indicated time points. (D) Ntn1+/+ and Ntn1+/− mice were injected i.p. with ZyA (1mg) and subsequently with vehicle or RvD1 (1 µg/mouse), and peritoneal exudates were collected at indicated time intervals. Results in A–D represent 2 independent experiments with n = 4–6 mice per treatment per time point expressed as mean.
Mentions: Because vagotomy reduced RvD1 levels, we tested whether RvD1 could rescue the hyperinflammatory response obtained with vagotomy. Indeed, results in Fig. 3 indicate that administration of RvD1 rescued the excessive increased PMN infiltration that resulted from vagotomy (caused by vagus nerve cutting). RvD1 stopped PMN influx in the vagotomized animals and regulated the exudate monocyte recruitment (Fig. 3 A). In these exudates, RvD1 also reduced TNF, IL-6, KC (IL-8 in humans), MIP-1α, and HMGB-1 (Fig. 3 B). Also, netrin-1 reduced Ri when given at either T0 (Fig. 4 A) or at the maximum PMN infiltration (Fig. 4 B). In both cases, netrin-1 shortened the time required to resolve inflammation.

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