Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation.
Excessive inflammation and tumour-necrosis factor (TNF) synthesis cause morbidity and mortality in diverse human diseases including endotoxaemia, sepsis, rheumatoid arthritis and inflammatory bowel disease. Highly conserved, endogenous mechanisms normally regulate the magnitude of innate immune responses and prevent excessive inflammation. The nervous system, through the vagus nerve, can inhibit significantly and rapidly the release of macrophage TNF, and attenuate systemic inflammatory responses. This physiological mechanism, termed the 'cholinergic anti-inflammatory pathway' has major implications in immunology and in therapeutics; however, the identity of the essential macrophage acetylcholine-mediated (cholinergic) receptor that responds to vagus nerve signals was previously unknown. Here we report that the nicotinic acetylcholine receptor alpha7 subunit is required for acetylcholine inhibition of macrophage TNF release. Electrical stimulation of the vagus nerve inhibits TNF synthesis in wild-type mice, but fails to inhibit TNF synthesis in alpha7-deficient mice. Thus, the nicotinic acetylcholine receptor alpha7 subunit is essential for inhibiting cytokine synthesis by the cholinergic anti-inflammatory pathway.
Wang
Hong
H
Laboratory of Biomedical Science, North Shore Long Island Jewish Research Institute, 350 Community Drive, Manhasset, New York 11030, USA.
Yu
Man
M
Ochani
Mahendar
M
Amella
Carol Ann
CA
Tanovic
Mahira
M
Susarla
Seenu
S
Li
Jian Hua
JH
Wang
Haichao
H
Yang
Huan
H
Ulloa
Luis
L
Al-Abed
Yousef
Y
Czura
Christopher J
CJ
Tracey
Kevin J
KJ
D000109:Acetylcholine / Q000494:pharmacology; D000375:Aging / Q000502:physiology; D000818:Animals; D002038:Bungarotoxins / Q000378:metabolism; D002478:Cells, Cultured; D004558:Electric Stimulation; D019446:Endotoxemia / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009538:Nicotine / Q000494:pharmacology; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014630:Vagus Nerve / Q000502:physiology; D064569:alpha7 Nicotinic Acetylcholine Receptor
D002038:Bungarotoxins; C579167:Chrna7 protein, human; C579166:Chrna7 protein, mouse; D021122:Protein Subunits; D012333:RNA, Messenger; D011978:Receptors, Nicotinic; D014409:Tumor Necrosis Factor-alpha; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine; D000109:Acetylcholine