Inflammatory responses to stimuli are essential body defenses against foreign threats. However, uncontrolled inflammation may result in serious health problems, which can be life-threatening. The α7 nicotinic acetylcholine receptor, a ligand-gated ion channel expressed in the nervous and immune systems, has an essential role in the control of inflammation. Activation of the macrophage α7 receptor by acetylcholine, nicotine, or other agonists, selectively inhibits production of pro-inflammatory cytokines while leaving anti-inflammatory cytokines undisturbed. The neural control of this regulation pathway was discovered recently and it was named the cholinergic anti-inflammatory pathway (CAP). When afferent vagus nerve terminals are activated by cytokines or other pro-inflammatory stimuli, the message travels through the afferent vagus nerve, resulting in action potentials traveling down efferent vagus nerve fibers in a process that eventually leads to macrophage α7 activation by acetylcholine and inhibition of pro-inflammatory cytokines production. The mechanism by which activation of α7 in macrophages regulates pro-inflammatory responses is subject of intense research, and important insights have thus been made. The results suggest that activation of the macrophage α7 controls inflammation by inhibiting NF-κB nuclear translocation, and activating the JAK2/STAT3 pathway among other suggested pathways. While the α7 is well characterized as a ligand-gated ion channel in neurons, whole-cell patch clamp experiments suggest that α7’s ion channel activity, defined as the translocation of ions across the membrane in response to ligands, is absent in leukocytes, and therefore, ion channel activity is generally assumed not to be required for the operation of the CAP. In this perspective, we briefly review macrophage α7 activation as it relates to the control of inflammation, and broaden the current view by providing single-channel currents as evidence that the α7 expressed in macrophages retains its ion translocation activity despite the absence of whole-cell currents. Whether this ion-translocating activity is relevant for the proper operation of the CAP or other important physiological processes remains obscure.
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We are very grateful for Dr. Roger Papke’s key suggestion of employing the positive allosteric modulator PNU-120596 in our cell-attached patch clamp experiments. This project was supported by the National Center for Research Resources (NCRR) grant U54RR026139, the National Institute on Minority Health and Health Disparities (NIMHD) grant 8U54MD007587-03, the National Institute of Neurological Disorders and Stroke (NINDS) grant U54NS0430311, the National Institute of General Medical Sciences (NIGMS) grant 1P20GM103642, and the National Institute of Mental Health (NIMH) grant P30MH075673-07. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health (NIH). Manuel Delgado-Vélez was supported by the University of Puerto Rico, Río Piedras Campus, Research Initiative for Scientific Enhancement (RISE) Program grant 2R25GM061151-5A1.
Conflict of Interest
The authors declare that they have no conflict of interest.
Alkondon M, Pereira EF, Cortes WS et al (1997) Choline is a selective agonist of alpha7 nicotinic acetylcholine receptors in the rat brain neurons. Eur J Neurosci 9:2734–2742CrossRefPubMedGoogle Scholar
Arias HR (1998) Binding sites for exogenous and endogenous non-competitive inhibitors of the nicotinic acetylcholine receptor. Biochim Biophys Acta 1376:173–220CrossRefPubMedGoogle Scholar
De Jonge WJ, van der Zanden EP, The FO et al (2005) Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway. Nat Immunol 6:844–851. doi:10.1038/ni1229CrossRefPubMedGoogle Scholar
Devillers-Thiéry A, Galzi JL, Eiselé JL et al (1993) Functional architecture of the nicotinic acetylcholine receptor: a prototype of ligand-gated ion channels. J Membr Biol 136:97–112CrossRefPubMedGoogle Scholar
DiPaola M, Czajkowski C, Karlin A (1989) The sidedness of the COOH terminus of the acetylcholine receptor delta subunit. J Biol Chem 264:15457–15463PubMedGoogle Scholar
Karlin A, Akabas MH (1995) Toward a structural basis for the function of nicotinic acetylcholine receptors and their cousins. Neuron 15:1231–1244CrossRefPubMedGoogle Scholar
Kim T-H, Kim S-J, Lee S-M (2014) Stimulation of the α7 nicotinic acetylcholine receptor protects against sepsis by inhibiting Toll-like receptor via phosphoinositide 3-kinase activation. J Infect Dis 209:1668–1677. doi:10.1093/infdis/jit669CrossRefPubMedGoogle Scholar
Le Novère N, Corringer P-J, Changeux J-P (2002) The diversity of subunit composition in nAChRs: evolutionary origins, physiologic and pharmacologic consequences. J Neurobiol 53:447–456. doi:10.1002/neu.10153CrossRefPubMedGoogle Scholar
Ochoa EL, Chattopadhyay A, McNamee MG (1989) Desensitization of the nicotinic acetylcholine receptor: molecular mechanisms and effect of modulators. Cell Mol Neurobiol 9:141–178CrossRefPubMedGoogle Scholar
Tsoyi K, Jang HJ, Kim JW et al (2011) Stimulation of alpha7 nicotinic acetylcholine receptor by nicotine attenuates inflammatory response in macrophages and improves survival in experimental model of sepsis through heme oxygenase-1 induction. Antioxid Redox Signal 14:2057–2070. doi:10.1089/ars.2010.3555CrossRefPubMedGoogle Scholar
Villiger Y, Szanto I, Jaconi S et al (2002) Expression of an alpha7 duplicate nicotinic acetylcholine receptor-related protein in human leukocytes. J Neuroimmunol 126:86–98CrossRefPubMedGoogle Scholar
Yoshikawa H, Kurokawa M, Ozaki N et al (2006) Nicotine inhibits the production of proinflammatory mediators in human monocytes by suppression of I-kappaB phosphorylation and nuclear factor-kappaB transcriptional activity through nicotinic acetylcholine receptor alpha7. Clin Exp Immunol 146:116–123. doi:10.1111/j.1365-2249.2006.03169.xPubMedCentralCrossRefPubMedGoogle Scholar
Zhang ZW, Vijayaraghavan S, Berg DK (1994) Neuronal acetylcholine receptors that bind alpha-bungarotoxin with high affinity function as ligand-gated ion channels. Neuron 12:167–177CrossRefPubMedGoogle Scholar