The alpha7 nicotinic acetylcholine receptor as a pharmacological target for inflammation

Abstract

The physiological regulation of the immune system encompasses comprehensive anti-inflammatory mechanisms that can be harnessed for the treatment of infectious and inflammatory disorders. Recent studies indicate that the vagal nerve, involved in control of heart rate, hormone secretion and gastrointestinal motility, is also an immunomodulator. In experimental models of inflammatory diseases, vagal nerve stimulation attenuates the production of proinflammatory cytokines and inhibits the inflammatory process. Acetylcholine, the principal neurotransmitter of the vagal nerve, controls immune cell functions via the alpha7 nicotinic acetylcholine receptor (alpha7nAChR). From a pharmacological perspective, nicotinic agonists are more efficient than acetylcholine at inhibiting the inflammatory signaling and the production of proinflammatory cytokines. This 'nicotinic anti-inflammatory pathway' may have clinical implications as treatment with nicotinic agonists can modulate the production of proinflammatory cytokines from immune cells. Nicotine has been tested in clinical trials as a treatment for inflammatory diseases such as ulcerative colitis, but the therapeutic potential of this mechanism is limited by the collateral toxicity of nicotine. Here, we review the recent advances that support the design of more specific receptor-selective nicotinic agonists that have anti-inflammatory effects while eluding its collateral toxicity.

Figure 1

The cholinergic anti-inflammatory surveillance. Hypothetical scheme of the vagus nerve continuously monitoring and modulating innate immune activation following ingestion, infection, and trauma. (1) During digestion, the commensal flora and dietary components activate the sensory afferent vagus nerve, which will transmit the information to the brain. In return, the brain may activate the efferent vagus nerve to modulate gastrointestinal macrophages. (2) The efferent vagus nerve also modulates systemic inflammatory responses through a mechanism involving an intact spleen. Upon infection or trauma, bacterial components or intracellular mediators (HMGB1, heat shock proteins, etc) activate macrophages to produce proinflammatory cytokines. (3) This will trigger afferent vagus nerve signaling. (4) In return, the brain will activate efferent vagus nerve to release acetylcholine, which can bind to the α7 acetylcholine receptor on macrophages and inhibit the production of proinflammatory cytokines. Interrogation marks indicate that although macrophages are found in the proximity of cholinergic fibers in the spleen and the intestine (De Jonge et al., 2005) there is currently no evidence demonstrating that parasympathetic neurons indeed innervate immune cells and further studies are needed to determine the physiological interaction between the vagus nerve and immune cells. HMGB1, high-mobility group box 1.

Figure 2

The α7 nicotinic acetylcholine receptor (α7 nAChR) structure. (a) The Chrna7 is located at the 15q14 chromosomal region. The gene comprises ten exons encompassing 138.5 kb that codifies for the α7 nAChR protein with an estimated MW 50 kDa. Six mRNA splice variants have been described in addition to the wild type α7-gene, though it is uncertain whether any of these transcripts are processed to functional protein. The gen Chrfam7a represents a partial duplication of the human Chrna7 exons 5 to 10. This partial duplicated gene is combined with four novel exons (A to D) to comprise a new gene named ‘Cholinergic Receptor FAMily with sequence similarity 7A' (Chrfam7a) or ‘hybrid α7'. To date, there is evidence that this gene is transcribed and processed to form a functional receptor. (b) The α7 nAChR has an N-terminal signal peptide and ligand-binding domain, four transmembrane domains (TM1-4), and a regulatory intracellular domain located between TM3 and TM4. (c) Nicotinic acetylcholine receptors (nAChRs) are a family of ligand-gated ion channels created by a diversity of subunits that form homo- or heteropentameric receptors with distinct pharmacological properties. Nicotinic receptors can functionally be differentiated into two principal classes that differ in their affinity for nicotine and α-bungarotoxin. Receptors that bind nicotine with high affinity, contain α2–α6 as ligand-binding subunits, and require β-subunits for proper activation. A second class of receptors (α7–α10) binds nicotine with low affinity; has high affinity for α-bungarotoxin, and functions as homomeric or heteromeric ion channels in vitro. The α7 nAChR forms homo-pentameric ion channel receptors and they appears to be the only α-bungarotoxin receptor identified in macrophages and mammalian brain, as α8-subunits appear to be expressed only in chick, and α9,10-subunits expression is limited to mechanosensory cochlear hair cells and the pituitary.

Figure 3

The cellular ‘nicotinic anti-inflammatory pathway'. Nicotine has been successfully used in clinical trials for the treatment of ulcerative colitis. Despite its pharmacological interest, little is known about the ‘nicotinic anti-inflammatory pathway' triggered by the α7 nAChR in immune cells. Two major pathways have been recently reported in macrophages. During infection or trauma, bacterial components (LPS, PGN, CpG-DNA, etc) or intracellular mediators (HMGB1, heat shock proteins, etc) trigger pro-inflammatory pathways that converge in the activation of the NF-κB, which will translocate into the nucleus and induce the transcriptional activation of a variety of inflammatory cytokines. Recent studies indicate that nicotine inhibits the production of pro-inflammatory cytokines in macrophages by preventing the activation of the NF-κB through a mechanism dependent on the α7 nAChR. In peritoneal macrophages, the α7 nAChR can recruit the tyrosine kinase Jak2 and promotes STAT3 phosphorylation and subsequent activation. The Jak2-STAT3 pathway can contribute to the anti-inflammatory potential of the α7 nAChR by inducing the expression of anti-inflammatory proteins such as SOCS3.

Figure 4

Chemical structure of selective cholinergic agonists and antagonists. Nicotinic agonists specifically targeting the α7 nAChR have been developed. Acetylcholine (a) can signal through acetylcholine signals through either (c) muscarinic (G protein-coupled receptors) or (b) nicotinic (ligand-gated ion channels) receptors. These receptors are characterized by using selective pharmacological agonists and antagonists for nicotinic (nicotine vs mecamylamine) and muscarinic (muscarine vs atropine) receptors. Nicotine, a more selective and stable cholinergic agonist, is more efficient than acetylcholine as an anti-inflammatory pharmacological strategy. (d) The anti-inflammatory potential of nicotine appears to be mediated by the α7 nAChR, and recent studies are currently focused on designing selective α7-agonists as a anti-inflammatory pharmacological strategy for the treatment of infectious and inflammatory disorders.