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Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis

Nature Medicine volume 10, pages 1216–1221 (2004)Cite this article

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.

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Figure 1: Cholinergic agonists inhibit human macrophages.
Figure 2: Nicotinic stimulation specifically inhibits HMGB1 release.
Figure 3: Nicotinic treatment prevents lethal endotoxemia.
Figure 4: Nicotinic stimulation prevents the NF-κB pathway.
Figure 5: Nicotine improves survival in 'established' sepsis.
Figure 6: The 'nicotinic anti-inflammatory pathway.'

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Acknowledgements

The authors are grateful for the suggestions of J. Li, R. Wagner, P. Wang, L. Mantell, J. Peña and H. Yang. This research was supported by the Faculty Awards Program of the North Shore Research Institute, the North Shore-LIJ GCRC, NIGMS and DARPA.

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Author notes

  1. Hong Wang and Hong Liao: These authors have contributed equally to this work.

Authors and Affiliations

  1. The Center for Immunology and Inflammation, North Shore-LIJ Research Institute, North Shore University Hospital, 350 Community Drive, Manhasset, New York, 11030, USA

    Hong Wang, Hong Liao, Marilou Justiniani, Yousef Al-Abed, Christine Metz & Luis Ulloa

  2. Center for Patient-Oriented Research, North Shore University Hospital, 350 Community Drive, Manhasset, New York, 11030, USA

    Mahendar Ochani, Lihong Yang & Kevin J Tracey

  3. Department of Surgery, North Shore University Hospital, 350 Community Drive, Manhasset, New York, 11030, USA

    Xinchun Lin & Edmund J Miller

  4. Department of Emergency Medicine, North Shore University Hospital, 350 Community Drive, Manhasset, New York, 11030, USA

    Haichao Wang

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Correspondence to Luis Ulloa.

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Competing interests

The authors have pending patents related to the potential value of the α7 nicotinic acetylcholine receptor for the treatment of inflammatory disorders.

Supplementary information

Supplementary Fig. 1

Cycloheximide did not block entoxin-induced HMGB1 extracellular release from macrophages (PDF 49 kb)

Supplementary Fig. 2

Nicotinic inhibits the activation of the NF–κB signaling induced by peptidoglycan from S. aureus (PDF 60 kb)

Supplementary Table 1

Effect of nicotinic treatment during lethal endotoxemia (PDF 9 kb)

Supplementary Table 2

Effect of nicotinic treatment during peritonitis (PDF 9 kb)

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Wang, H., Liao, H., Ochani, M. et al. Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nat Med 10, 1216–1221 (2004). https://doi.org/10.1038/nm1124

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