Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis

Hong Wang; Hong Liao; Mahendar Ochani; Marilou Justiniani; Xinchun Lin; Lihong Yang; Yousef Al-Abed; Haichao Wang; Christine Metz; Edmund J. Miller; Kevin J. Tracey; Luis Ulloa

doi:https://doi.org/10.1038/nm1124

Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis

Hong Wang, Hong Liao, Mahendar Ochani, Marilou Justiniani, Xinchun Lin, Lihong Yang, Yousef Al-Abed, Haichao Wang, Christine Metz, Edmund J. Miller, Kevin J. Tracey, Luis Ulloa

Research output: Contribution to journal › Article › peer-review

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Abstract

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-α). Nicotinic stimulation prevents activation of the NF-κB pathway and inhibits HMGB1 secretion through a specific 'nicotinic anti-inflammatory pathway' that requires the α7 nicotinic acetylcholine receptor (α7nAChR). 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 α7nAChR might have therapeutic potential for the treatment of sepsis.

Original language	American English
Pages (from-to)	1216-1221
Number of pages	6
Journal	Nature Medicine
Volume	10
Issue number	11
DOIs	https://doi.org/10.1038/nm1124
State	Published - Nov 2004
Externally published	Yes

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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@article{6668d883d0b54ffeaadd69cb6a1c0770,

title = "Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis",

abstract = "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-α). Nicotinic stimulation prevents activation of the NF-κB pathway and inhibits HMGB1 secretion through a specific 'nicotinic anti-inflammatory pathway' that requires the α7 nicotinic acetylcholine receptor (α7nAChR). 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 α7nAChR might have therapeutic potential for the treatment of sepsis.",

author = "Hong Wang and Hong Liao and Mahendar Ochani and Marilou Justiniani and Xinchun Lin and Lihong Yang and Yousef Al-Abed and Haichao Wang and Christine Metz and Miller, {Edmund J.} and Tracey, {Kevin J.} and Luis Ulloa",

note = "Funding Information: This study was supported by Agence Nationale de Recherches sur le SIDA et les Hepatites (ANRS) , France; contract ANRS12-12 . M. A. Jenabian is supported by a CANFAR/CTN postdoctoral fellowship.",

year = "2004",

month = nov,

doi = "https://doi.org/10.1038/nm1124",

language = "American English",

volume = "10",

pages = "1216--1221",

journal = "Nature Medicine",

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T1 - Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis

AU - Wang, Hong

AU - Liao, Hong

AU - Ochani, Mahendar

AU - Justiniani, Marilou

AU - Lin, Xinchun

AU - Yang, Lihong

AU - Al-Abed, Yousef

AU - Wang, Haichao

AU - Metz, Christine

AU - Miller, Edmund J.

AU - Tracey, Kevin J.

AU - Ulloa, Luis

N1 - Funding Information: This study was supported by Agence Nationale de Recherches sur le SIDA et les Hepatites (ANRS) , France; contract ANRS12-12 . M. A. Jenabian is supported by a CANFAR/CTN postdoctoral fellowship.

PY - 2004/11

Y1 - 2004/11

N2 - 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-α). Nicotinic stimulation prevents activation of the NF-κB pathway and inhibits HMGB1 secretion through a specific 'nicotinic anti-inflammatory pathway' that requires the α7 nicotinic acetylcholine receptor (α7nAChR). 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 α7nAChR might have therapeutic potential for the treatment of sepsis.

AB - 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-α). Nicotinic stimulation prevents activation of the NF-κB pathway and inhibits HMGB1 secretion through a specific 'nicotinic anti-inflammatory pathway' that requires the α7 nicotinic acetylcholine receptor (α7nAChR). 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 α7nAChR might have therapeutic potential for the treatment of sepsis.

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Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis

Abstract

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