Nicotinic Modulation of Innate Immune Pathways Via α7 Nicotinic Acetylcholine Receptor

Abstract

The major addictive component of tobacco, nicotine, exerts anti-inflammatory effects in multiple cell types and may benefit neurons in various degenerative disorders, such as Alzheimer's and Parkinson's disease, in which an inflammation-related mechanism is implicated. Among the various nicotinic acetylcholine receptors, α7, which has been identified in both neurons and immune cells and has high permeability to calcium, is believed to contribute significantly to nicotinic anti-inflammatory and neuron-protective effects. Although nicotine has been used in clinical trials for the treatment of some inflammatory diseases such as ulcerative colitis, the molecular mechanisms of its actions are largely unknown. In this review, we provide current evidence for nicotine's modulation of multiple immune pathways via α7 nAChRs in both neurons and immune cells. Understanding the mechanism of the nicotinic anti-inflammatory effect and neuron-protective function may guide the development of novel medicines for infectious and neuron-degenerative diseases.

Identification and Characterization of Poly(I:C)-induced Molecular Responses Attenuated by Nicotine in Mouse Macrophages

“…Third, they have different subcellular locations: TLR4 on cell surfaces and TLR3 in endolysosomal compartments (Le Goffic et al, 2007). In TLR4-activated macrophages, nicotine apparently suppresses NF-kB activation and proinflammatory cytokine expression through a7-nAChR Wang et al, 2004;Cui and Li, 2010). GTS-21, a selective a7-nAChR agonist, can attenuate TLRs-triggered cytokine expression (Rosas-Ballina et al, 2009).…”

“…Toll-like receptor (TLR) pathways, especially TLR4, the receptor for Gram-negative bacterial lipopolysaccharide (LPS) (Wittebole et al, 2010), a7-nAChR, and multiple signaling pathways (Sugano et al, 1998;Wang et al, 2004;de Jonge et al, 2005;Arredondo et al, 2006;Hamano et al, 2006;Park et al, 2008;Cui and Li, 2010) are involved in the anti-inflammatory effect of nicotine. Stimulation of TLRs activates transcription factor nuclear factor-kB (NF-kB) and stress-activated protein kinases (Slack et al, 2000;Beutler, 2004) involved in the expression of mRNAs of inflammatory cytokines.…”

“…Stimulation of TLRs activates transcription factor nuclear factor-kB (NF-kB) and stress-activated protein kinases (Slack et al, 2000;Beutler, 2004) involved in the expression of mRNAs of inflammatory cytokines. In a sepsis model, nicotine inhibited TLR4-induced inflammation and improved survival by interacting with a7-nAChR (Wang et al, , 2004Cui and Li, 2010). Treatment with cholinergic agonist(s) activates the JAK2-STAT3 pathway and suppresses NF-kB activity (de Jonge et al, 2005;Yoshikawa et al, 2006).…”

Activation of Nicotinic Acetylcholine Receptors Decreases Apoptosis in Human and Female Murine Pancreatic Islets

“…They are implicated in neuronal processes such as synaptic transmission but also in the regulation of neuronal cell death in response to injuries such as hypoxia and glutamate excitotoxicity (4) and, outside the central nervous system, in the modulation of peripheral inflammation (5,6). Their presence has been demonstrated on human and murine ␤-cells (7,8).…”

Is-there a place for vagus nerve stimulation in inflammatory bowel diseases?

“…This approach can be obtained i) pharmacologically with α7nAChR agonists such as nicotine (Cui & Li, 2010), GTS21 (Kox et al, 2011), and AR-R17779 (van Westerloo et al, 2006), activation of the central cholinergic pathway with an AChesterase inhibitor (galantamine) (Pavlov et al, 2009) or CNI-1492, a cytokine inhibitor and synthetic guanylhydrazone mitogenactivated protein kinase blocker (Tracey, 1998), ii) high fat enteral feeding inducing the release of CCK that activates CCK1 vagal afferents thus activating the CAP (Luyer et al, 2005), iii) complementary and alternative medicines such as meditation, yoga, acupuncture, hypnosis, known to activate the VN (Keefer et al, 2013), iv) physical exercise (Mora et al, 2007), v) VNS which appears as the most interesting tool because already validated in drug resistant epilepsy and depression in human with very few side effects (Bonaz et al, 2013).…”