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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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.)
The authors declare no competing financial interests.
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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). https://doi.org/10.1038/ni1229
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