Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway

An Erratum to this article was published on 01 September 2005


Acetylcholine released by efferent vagus nerves inhibits macrophage activation. Here we show that the anti-inflammatory action of nicotinic receptor activation in peritoneal macrophages was associated with activation of the transcription factor STAT3. STAT3 was phosphorylated by the tyrosine kinase Jak2 that was recruited to the α7 subunit of the nicotinic acetylcholine receptor. The anti-inflammatory effect of nicotine required the ability of phosphorylated STAT3 to bind and transactivate its DNA response elements. In a mouse model of intestinal manipulation, stimulation of the vagus nerve ameliorated surgery-induced inflammation and postoperative ileus by activating STAT3 in intestinal macrophages. We conclude that the vagal anti-inflammatory pathway acts by α7 subunit–mediated Jak2-STAT3 activation.

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Figure 1: Nicotine attenuates peritoneal macrophage activation and induces phosphorylation of STAT3 and SOCS3 expression.
Figure 2: Inhibition of macrophage activation by nicotine requires transactivation of STAT3 but not SOCS3 expression.
Figure 3: STAT3 phosphorylation by nicotine is prevented by α7-selective nAChR antagonists.
Figure 4: Nicotine-induced STAT3 phosphorylation occurs through activation of Jak2 that is recruited to the α7 nAChR subunit.
Figure 5: Perioperative electrical stimulation of the left cervical vagus nerve prevents gastroparesis 24 h after surgery with intestinal manipulation in mice.
Figure 6: Vagal stimulation reduces intestinal manipulation-induced proinflammatory mediator expression and release in vivo, independent of IL-10 production.
Figure 7: Stimulation of the vagus nerve activates STAT3 in intestinal macrophages in muscularis tissue.
Figure 8: Stimulation of the vagus nerve fails to reduce inflammation in LysM-Stat3fl/− mice.


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We thank T. van der Poll, C. van 't Veer and T. O'Toole for discussions and critical reading of the manuscript; F. van Hemert and C. Veeris for assistance in the gastric emptying studies; I. Touw and T. Hirano for providing STAT3 constructs; B. Clausen and I. Förster for providing LysMcre mice; and L. Patterson for technical help with immunohistochemistry. Supported by the Technology Foundation (STW), applied science division of the Netherlands Organization for Scientific Research (NOW), the technology program of the Ministry of Economic Affairs (NWO-STW; AKG.5727; F.O.T. and R.M.v.d.W.) and the National Institutes of Health (DK57242 and DK4738; H.R.B.)

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Correspondence to Wouter J de Jonge.

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Supplementary information

Supplementary Fig. 1

Vagal nerve stimulation reduces recruitment of inflammatory infiltrates to the intestinal muscularis by activating peripheral nicotinic acetylcholine receptors. (PDF 1050 kb)

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de Jonge, W., van der Zanden, E., The, F. et al. Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway. Nat Immunol 6, 844–851 (2005).

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