The Cholinergic Anti-inflammatory Pathway: A Missing Link in Neuroimmunomodulation

Laboratory of Biomedical Science, North Shore LIJ-Research Institute, Manhasset, NY 11030, USA.
Molecular Medicine (Impact Factor: 4.51). 05/2003; 9(5-8):125-34.
Source: PubMed

ABSTRACT This review outlines the mechanisms underlying the interaction between the nervous and immune systems of the host in response to an immune challenge. The main focus is the cholinergic anti-inflammatory pathway, which we recently described as a novel function of the efferent vagus nerve. This pathway plays a critical role in controlling the inflammatory response through interaction with peripheral a7 subunit-containing nicotinic acetylcholine receptors expressed on macrophages. We describe the modulation of systemic and local inflammation by the cholinergic anti-inflammatory pathway and its function as an interface between the brain and the immune system. The clinical implications of this novel mechanism also are discussed.

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Available from: Christopher Czura, Sep 28, 2015
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    • "The afferent and efferent limbs of the vagus nerve constitute the cholinergic antiinflammatory pathway (Pavlov et al., 2003; Tracey, 2002) which acts as an interface "
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    ABSTRACT: Background and purpose: In the search for safer and effective anti-inflammatory agents, we investigated the effect of methyl indoline-3-propionate and indoline-3-(3-aminopropyl) carbamates on LPS-induced lung injury and pro-inflammatory cytokines in mice. Their mechanism of action was determined in murine peritoneal macrophages. Experimental approach: Lung injury was induced by intratracheal infusion of LPS and assessed by the change in lung weight and structure by light microscopy after staining by haematoxylin and eosin. In LPS-activated macrophages, MAPK proteins and IκBα were measured by Western blotting and the transcription factors, AP-1 and NF-κB by electromobility shift assay. Cytokines in the plasma and spleen of mice injected with LPS were measured by elisa-based assay. Key results: AN917 and AN680 (1-10 pM) decreased TNF-α protein in macrophages by inhibiting phosphorylation of p38 MAPK, IκBα degradation and activation of AP-1 and NF-κB without affecting cell viability. In vivo, these compounds (10 μmol · kg(-1)) markedly decreased lung injury induced by LPS and the elevation of TNF-α and IL-6 in lung, plasma and spleen. Activation of α-7nACh receptors contributed to the reduction of TNF-α by AN917, which inhibited AChE in the spleen by 35%. Conclusion and implications: Indoline carbamates are potent inhibitors of pro-inflammatory mediators in murine macrophages and in mice injected with LPS, acting via the p38 MAPK, AP-1 and NF-κB cascades. Indirect α-7nACh receptor activation by AN917, through inhibition of AChE, contributes to its anti-inflammatory effect. Indoline carbamates may have therapeutic potential for lung injury and other diseases associated with chronic inflammation without causing immunosuppression.
    British Journal of Pharmacology 10/2014; 172(4). DOI:10.1111/bph.12982 · 4.84 Impact Factor
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    • "The vagus nerve has an important role in this process. Previous research demonstrated that electrical stimulation of the efferent vagus nerve inhibits pro-inflammatory cytokines through the “cholinergic anti-inflammatory pathway” [7,15-17]. Even though, previous studies have shown that vagus nerve stimulation protects against excessive inflammatory response in hemorrhagic shock, the effect on coagulation has been scarcely investigated [18]. "
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    ABSTRACT: Introduction Inflammation plays a major role in the multifactorial process of trauma associated coagulopathy. The vagus nerve regulates the cholinergic anti-inflammatory pathway. We hypothesized that efferent vagus nerve stimulation (VNS) can improve coagulopathy by modulating the inflammatory response to hemorrhage. Methods Wistar rats (n = 24) were divided in 3 groups: Group (G1) Sham hemorrhagic shock (HS); (G2) HS w/o VNS; (G3) HS followed by division of the vagus nerves and VNS of the distal stumps. Hemorrhage (45% of baseline MAPx15 minutes) was followed by normotensive resuscitation with LR. Vagus nerves were stimulated (3.5 mA, 5 Hz) for 30 sec 7 times. Samples were obtained at baseline and at 60 minutes for thromboelastometry (Rotem®) and cytokine assays (IL-1 and IL-10). ANOVA was used for statistical analysis; significance was set at p < 0.05. Results Maximum clot firmness (MCF) significantly decreased in G2 after HS (71.5 ± 1.5 vs. 64 ± 1.6) (p < 0.05). MCF significantly increased in G3 compared to baseline (67.3 ± 2.7 vs. 71.5 ± 1.2) (p < 0.05). G3 also showed significant improvement in Alfa angle, and Clot Formation Time (CFT) compared to baseline. IL-1 increased significantly in group 2 and decrease in group 3, while IL-10 increased in group 3 (p < 0.05). Conclusions Electrical stimulation of efferent vagus nerves, during resuscitation (G3), decreases inflammatory response to hemorrhage and improves coagulation.
    Journal of Trauma Management & Outcomes 09/2014; 8(1):15. DOI:10.1186/1752-2897-8-15
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    • "Activation of α7nAChR exert anti-inflammatory effects and ameliorates inflammation in a variety of in vivo disease models, including sepsis, arthritis, and myocardial ischemia [36] [37] [38]. Exogenous treatment with ACh agonists reduces experimentally induced inflammation suggesting that a decline in cholinergic neurotransmission following neuronal stress probably increases neuroinflammatory response [38]. However, no studies to date have investigated the effect of relative blockade of cholinergic muscarinic and nicotinic receptors on behavioural outcome, oxidative stress and memory dysfunction following GCI/R injury. "
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    ABSTRACT: Global cerebral ischemia/reperfusion (GCI/R) injury encompasses complex pathophysiological sequalae, inducing loss of hippocampal neurons and behavioural deficits. Progressive neuronal death and memory dysfunctions culminate from several different mechanisms like oxidative stress, excitotoxicity, neuroinflammation and cholinergic hypofunction. Experimental evidences point to the beneficial effects of cholinomimetic agents such as rivastigmine and galantamine in improving memory outcomes following GCI/R injury. However, the direct implications of muscarinic and nicotinic receptor blockade during global cerebral ischemia/reperfusion injury has not been investigated. Therefore, we evaluated the relative involvement of muscarinic and nicotinic receptors in spatial/associative memory functions and neuronal damage during global cerebral ischemia reperfusion injury. The outcomes of present study support the idea that preservation of both muscarinic and nicotinic receptor functions is essential to alleviate hippocampal neuronal death in CA1 region following global cerebral ischemia/reperfusion injury.
    Nitric Oxide 08/2014; 43. DOI:10.1016/j.niox.2014.08.009 · 3.52 Impact Factor
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