Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway.
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.
de Jonge
Wouter J
WJ
Division of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
van der Zanden
Esmerij P
EP
The
Frans O
FO
Bijlsma
Maarten F
MF
van Westerloo
David J
DJ
Bennink
Roelof J
RJ
Berthoud
Hans-Rudolf
HR
Uematsu
Satoshi
S
Akira
Shizuo
S
van den Wijngaard
Rene M
RM
Boeckxstaens
Guy E
GE
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007249:Inflammation; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D053614:Janus Kinase 2; D053616:Janus Kinase 3; D007962:Leukocytes / Q000166:cytology; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009538:Nicotine / Q000737:chemistry / Q000494:pharmacology; D010586:Phagocytes / Q000166:cytology; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D014630:Vagus Nerve / Q000276:immunology* / Q000473:pathology*; D064569:alpha7 Nicotinic Acetylcholine Receptor
D000893:Anti-Inflammatory Agents; C579166:Chrna7 protein, mouse; C579165:Chrna7 protein, rat; D004268:DNA-Binding Proteins; D015850:Interleukin-6; C507936:Jak3 protein, rat; D011518:Proto-Oncogene Proteins; D011978:Receptors, Nicotinic; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C494088:Stat3 protein, rat; D015534:Trans-Activators; D064569:alpha7 Nicotinic Acetylcholine Receptor; D016753:Interleukin-10; D009538:Nicotine; D011505:Protein-Tyrosine Kinases; C507926:Jak2 protein, mouse; C507927:Jak2 protein, rat; C507935:Jak3 protein, mouse; D053614:Janus Kinase 2; D053616:Janus Kinase 3; D000109:Acetylcholine