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 alpha7 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 alpha7 subunit-mediated Jak2-STAT3 activation.

The cholinergic nervous system attenuates the production of pro-inflammatory cytokines and inhibits inflammatory processes. Hence, in animal models of intestinal inflammation, such as postoperative ileus and dextran sulfate sodium-induced colitis, vagus nerve stimulation ameliorates disease activity. On the other hand, in infectious models of microbial peritonitis, vagus nerve activation seemingly acts counteractive; it impairs bacterial clearance and increases mortality. It is originally indicated that the key mediator of the cholinergic anti-inflammatory pathway, acetylcholine (ACh), inhibits cytokine release directly via the alpha7 nicotinic ACh receptor (nAChR) expressed on macrophages. However, more recent data also point towards the vagus nerve as an indirect modulator of innate inflammatory processes, exerting its anti-inflammatory effects via postganglionic modulation of immune cells in primary immune organs. This review discusses advances in the possible mechanisms by which the vagus nerve can mediate the immune response, and the role of nAChR activation and signalling on macrophages and other immune cells.

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The role of STAT3 in infectious diseases remains undetermined, in part because unphosphorylated STAT3 has been considered an inactive protein. Here, we report that unphosphorylated STAT3 contributes to cholinergic anti-inflammation, prevents systemic inflammation, and improves survival in sepsis. Bacterial endotoxin induced STAT3 tyrosine phosphorylation in macrophages. Both alpha7 nicotinic receptor (alpha7nAChR) activation and inhibition of JAK2 blunt STAT3 phosphorylation. Inhibition of STAT3 phosphorylation mimicked the alpha7nAChR signaling, inhibiting NF-κB and cytokine production in macrophages. Transfection of macrophages with the dominant-negative mutant STAT3F, to prevent its tyrosine phosphorylation, reduced TNF production but did not prevent the alpha7nAChR signaling. However, inhibition of STAT3 protein expression enhanced cytokine production and abrogated alpha7nAChR signaling. Alpha7nAChR controls TNF production in macrophages through a mechanism that requires STAT3 protein expression, but not its tyrosine phosphorylation. In vivo, inhibition of STAT3 tyrosine phosphorylation by stattic prevented systemic inflammation and improved survival in experimental sepsis. Stattic also prevented the production of late mediators of sepsis and improved survival in established sepsis. These results reveal the immunological implications of tyrosine-unphosphorylated STAT3 in infectious diseases.

Background and purpose:In various models vagus nerve activation has been shown to ameliorate intestinal inflammation, via nicotinic acetylcholine receptors (nAChRs) expressed on immune cells. As the a7 nAChR has been put forward to mediate this effect, we studied the effect of nicotine and two selective a7 nAChR agonists (AR-R17779, (-)-spiro[1-azabicyclo[2.2.2] octane-3,5′-oxazolidin-2′-one and GSK1345038A) on disease severity in two mouse models of experimental colitis. Experimental approach: Colitis was induced by administration of 1.5% dextran sodium sulphate (DSS) in drinking water or 2 mg 2,4,6-trinitrobenzene sulphonic acid (TNBS) intrarectally. Nicotine (0.25 and 2.50 mmol·kg -1