Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis.
Physiological anti-inflammatory mechanisms can potentially be exploited for the treatment of inflammatory disorders. Here we report that the neurotransmitter acetylcholine inhibits HMGB1 release from human macrophages by signaling through a nicotinic acetylcholine receptor. Nicotine, a selective cholinergic agonist, is more efficient than acetylcholine and inhibits HMGB1 release induced by either endotoxin or tumor necrosis factor-alpha (TNF-alpha). Nicotinic stimulation prevents activation of the NF-kappaB pathway and inhibits HMGB1 secretion through a specific 'nicotinic anti-inflammatory pathway' that requires the alpha7 nicotinic acetylcholine receptor (alpha7nAChR). In vivo, treatment with nicotine attenuates serum HMGB1 levels and improves survival in experimental models of sepsis, even when treatment is started after the onset of the disease. These results reveal acetylcholine as the first known physiological inhibitor of HMGB1 release from human macrophages and suggest that selective nicotinic agonists for the alpha7nAChR might have therapeutic potential for the treatment of sepsis.
Wang
Hong
H
The Center for Immunology and Inflammation, North Shore-LIJ Research Institute, North Shore University Hospital, 350 Community Drive, Manhasset, New York 11030, USA.
Liao
Hong
H
Ochani
Mahendar
M
Justiniani
Marilou
M
Lin
Xinchun
X
Yang
Lihong
L
Al-Abed
Yousef
Y
Wang
Haichao
H
Metz
Christine
C
Miller
Edmund J
EJ
Tracey
Kevin J
KJ
Ulloa
Luis
L
D000109:Acetylcholine / Q000819:agonists / Q000378:metabolism*; D000818:Animals; D002432:Cecum / Q000293:injuries; D005455:Fluorescent Antibody Technique; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D008070:Lipopolysaccharides; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D015213:Neuroimmunomodulation / Q000502:physiology; D009538:Nicotine / Q000378:metabolism* / Q000627:therapeutic use*; D009841:Oligonucleotides; D011978:Receptors, Nicotinic / Q000378:metabolism*; D018805:Sepsis / Q000188:drug therapy* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D064569:alpha7 Nicotinic Acetylcholine Receptor
C579167:Chrna7 protein, human; C579166:Chrna7 protein, mouse; D024243:HMGB1 Protein; D008070:Lipopolysaccharides; D009841:Oligonucleotides; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine; D000109:Acetylcholine