Abstract
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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References
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 9:2734–2742
Arias HR (1998) Binding sites for exogenous and endogenous non-competitive inhibitors of the nicotinic acetylcholine receptor. Biochim Biophys Acta 1376:173–220
Benfante R, Antonini RA, De Pizzol M et al (2011) Expression of the α7 nAChR subunit duplicate form (CHRFAM7A) is down-regulated in the monocytic cell line THP-1 on treatment with LPS. J Neuroimmunol 230:74–84. doi:10.1016/j.jneuroim.2010.09.008
Borovikova LV, Ivanova S, Zhang M et al (2000) Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405:458–462. doi:10.1038/35013070
Brown KC, Lau JK, Dom AM et al (2012) MG624, an α7-nAChR antagonist, inhibits angiogenesis via the Egr-1/FGF2 pathway. Angiogenesis 15:99–114. doi:10.1007/s10456-011-9246-9
Cartaud J, Cartaud A, Kordeli E et al (2000) The torpedo electrocyte: a model system to study membrane-cytoskeleton interactions at the postsynaptic membrane. Microsc Res Tech 49:73–83. doi:10.1002/(SICI)1097-0029(20000401)49:1<73::AID-JEMT8>3.0.CO;2-L
Changeux JP, Edelstein SJ (1998) Allosteric receptors after 30 years. Neuron 21:959–980
Changeux JP, Devillers-Thiéry A, Galzi JL, Bertrand D (1992) New mutants to explore nicotinic receptor functions. Trends Pharmacol Sci 13:299–301
Charpantier E, Wiesner A, Huh K-H et al (2005) Alpha7 neuronal nicotinic acetylcholine receptors are negatively regulated by tyrosine phosphorylation and Src-family kinases. J Neurosci 25:9836–9849. doi:10.1523/JNEUROSCI. 3497-05.2005
Cockcroft VB, Osguthorpe DJ, Barnard EA et al (1990) Ligand-gated ion channels. Homology and diversity. Mol Neurobiol 4:129–169. doi:10.1007/BF02780338
Cooper E, Couturier S, Ballivet M (1991) Pentameric structure and subunit stoichiometry of a neuronal nicotinic acetylcholine receptor. Nature 350:235–238. doi:10.1038/350235a0
Corringer PJ, Le Novère N, Changeux JP (2000) Nicotinic receptors at the amino acid level. Annu Rev Pharmacol Toxicol 40:431–458. doi:10.1146/annurev.pharmtox.40.1.431
daCosta CJB, Free CR, Corradi J et al (2011) Single-channel and structural foundations of neuronal α7 acetylcholine receptor potentiation. J Neurosci 31:13870–13879. doi:10.1523/JNEUROSCI. 2652-11.2011
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/ni1229
De Lucas-Cerrillo AM, Maldifassi MC, Arnalich F et al (2011) Function of partially duplicated human α77 nicotinic receptor subunit CHRFAM7A gene: potential implications for the cholinergic anti-inflammatory response. J Biol Chem 286:594–606. doi:10.1074/jbc.M110.180067
Delgado-Vélez M, Lugo-Chinchilla A, Lizardo L et al (2008) Chronic exposure of human macrophages in vitro to morphine and methadone induces a putative tolerant/dependent state. J Neuroimmunol 196:94–100. doi:10.1016/j.jneuroim.2008.03.004
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 136:97–112
DiPaola M, Czajkowski C, Karlin A (1989) The sidedness of the COOH terminus of the acetylcholine receptor delta subunit. J Biol Chem 264:15457–15463
Galzi JL, Revah F, Bessis A, Changeux JP (1991) Functional architecture of the nicotinic acetylcholine receptor: from electric organ to brain. Annu Rev Pharmacol Toxicol 31:37–72. doi:10.1146/annurev.pa.31.040191.000345
Gilbert D, Lecchi M, Arnaudeau S et al (2009) Local and global calcium signals associated with the opening of neuronal alpha7 nicotinic acetylcholine receptors. Cell Calcium 45:198–207. doi:10.1016/j.ceca.2008.10.003
Hurst RS, Hajós M, Raggenbass M et al (2005) A novel positive allosteric modulator of the alpha7 neuronal nicotinic acetylcholine receptor: in vitro and in vivo characterization. J Neurosci 25:4396–4405. doi:10.1523/JNEUROSCI. 5269-04.2005
Itier V, Bertrand D (2001) Neuronal nicotinic receptors: from protein structure to function. FEBS Lett 504:118–125
Joe Y, Kim HJ, Kim S et al (2011) Tristetraprolin mediates anti-inflammatory effects of nicotine in lipopolysaccharide-stimulated macrophages. J Biol Chem 286:24735–24742. doi:10.1074/jbc.M110.204859
Kalamida D, Poulas K, Avramopoulou V et al (2007) Muscle and neuronal nicotinic acetylcholine receptors. Structure, function and pathogenicity. FEBS J 274:3799–3845. doi:10.1111/j.1742-4658.2007.05935.x
Karlin A (2002) Emerging structure of the nicotinic acetylcholine receptors. Nat Rev Neurosci 3:102–114. doi:10.1038/nrn731
Karlin A, Akabas MH (1995) Toward a structural basis for the function of nicotinic acetylcholine receptors and their cousins. Neuron 15:1231–1244
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/jit669
Le Novère N, Corringer PJ, Changeux JP (1999) Improved secondary structure predictions for a nicotinic receptor subunit: incorporation of solvent accessibility and experimental data into a two-dimensional representation. Biophys J 76:2329–2345. doi:10.1016/S0006-3495(99)77390-X
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.10153
Lueders C, Danne O, Müller C et al (2007) Evaluation of a chemiluminescent assay for analysis of choline in human plasma and whole blood. Lab Med 38:726–728. doi:10.1309/1N2NAYWQ53QVR6FX
Maldifassi MC, Atienza G, Arnalich F et al (2014) A new IRAK-M-mediated mechanism implicated in the anti-inflammatory effect of nicotine via α7 nicotinic receptors in human macrophages. PLoS ONE 9:e108397. doi:10.1371/journal.pone.0108397
Ochoa EL, Chattopadhyay A, McNamee MG (1989) Desensitization of the nicotinic acetylcholine receptor: molecular mechanisms and effect of modulators. Cell Mol Neurobiol 9:141–178
Papke RL (2014) Merging old and new perspectives on nicotinic acetylcholine receptors. Biochem Pharmacol 89:1–11. doi:10.1016/j.bcp.2014.01.029
Parrish WR, Rosas-Ballina M, Gallowitsch-Puerta M et al (2008) Modulation of TNF release by choline requires alpha7 subunit nicotinic acetylcholine receptor-mediated signaling. Mol Med 14:567–574. doi:10.2119/2008-00079.Parrish
Paterson D, Nordberg A (2000) Neuronal nicotinic receptors in the human brain. Prog Neurobiol 61:75–111
Paulo JA, Brucker WJ, Hawrot E (2009) Proteomic analysis of an alpha7 nicotinic acetylcholine receptor interactome. J Proteome Res 8:1849–1858. doi:10.1021/pr800731z
Peña G, Cai B, Liu J et al (2010) Unphosphorylated STAT3 modulates alpha 7 nicotinic receptor signaling and cytokine production in sepsis. Eur J Immunol 40:2580–2589. doi:10.1002/eji.201040540
Rosas-Ballina M, Olofsson PS, Ochani M et al (2011) Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit. Science 334:98–101. doi:10.1126/science.1209985
Russo P, Taly A (2012) α7-Nicotinic acetylcholine receptors: an old actor for new different roles. Curr Drug Targets 13:574–578
Schaal C, Chellappan SP (2014) Nicotine-mediated cell proliferation and tumor progression in smoking-related cancers. Mol Cancer Res 12:14–23. doi:10.1158/1541-7786.MCR-13-0541
Shen J, Yakel JL (2009) Nicotinic acetylcholine receptor-mediated calcium signaling in the nervous system. Acta Pharmacol Sin 30:673–680. doi:10.1038/aps.2009.64
Skok MV (2009) Editorial: To channel or not to channel? Functioning of nicotinic acetylcholine receptors in leukocytes. J Leukoc Biol 86:1–3. doi:10.1189/JLB.0209106
Sundman E, Olofsson PS (2014) Neural control of the immune system. Adv Physiol Educ 38:135–139
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.2010.3555
Villiger Y, Szanto I, Jaconi S et al (2002) Expression of an alpha7 duplicate nicotinic acetylcholine receptor-related protein in human leukocytes. J Neuroimmunol 126:86–98
Wang H, Yu M, Ochani M et al (2003) Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature 421:384–388. doi:10.1038/nature01339
Wang H, Liao H, Ochani M et al (2004) Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nat Med 10:1216–1221. doi:10.1038/nm1124
Wang Y, Xiao C, Indersmitten T et al (2014) The duplicated α7 subunits assemble and form functional nicotinic receptors with the full-length α7. J Biol Chem 289:26451–26463. doi:10.1074/jbc.M114.582858
Yang J, Liao X, Agarwal MK et al (2007) Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFkappaB. Genes Dev 21:1396–1408. doi:10.1101/gad.1553707
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.x
Zhang ZW, Vijayaraghavan S, Berg DK (1994) Neuronal acetylcholine receptors that bind alpha-bungarotoxin with high affinity function as ligand-gated ion channels. Neuron 12:167–177
Acknowledgments
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.
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Báez-Pagán, C.A., Delgado-Vélez, M. & Lasalde-Dominicci, J.A. Activation of the Macrophage α7 Nicotinic Acetylcholine Receptor and Control of Inflammation. J Neuroimmune Pharmacol 10, 468–476 (2015). https://doi.org/10.1007/s11481-015-9601-5
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DOI: https://doi.org/10.1007/s11481-015-9601-5