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: 4.82). 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.

Download full-text


Available from: Christopher Czura, Aug 17, 2015
  • Source
    • "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 "
    [Show abstract] [Hide abstract]
    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 · 4.99 Impact Factor
  • Source
    • "Because the penetration of systemic MLA to the CNS is negligible (Medhurst et al., 2008; Turek et al., 1995), these findings suggest that the vagus nerve mediates this effect from the spinal cord to the periphery with the involvement of α7 nAChRs. This is consistent with the inhibitory effect of the distal vagus nerve, on the cytokine response in the inflamed hind paw (Borovikova et al., 2000; Pavlov et al., 2003) and with the presence of α7 nAChRs on peripheral immune cells. The activation of α7 nAChRs is a well-documented mechanism for the suppression of inflammatory and neuropathic pain (Loram et al., 2012; Medhurst et al., 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: In this study the role of P2Y12 receptors (P2Y12R) were explored in rodent models of inflammatory and neuropathic pain and in acute thermal nociception. In correlation with their activity to block the recombinant human P2Y12R, the majority of P2Y12R antagonists alleviated mechanical hyperalgesia dose-dependently, following intraplantar CFA injection, and after partial ligation of the sciatic nerve in rats. They also caused an increase in thermal nociceptive threshold in the hot plate test. Among the six P2Y12R antagonists evaluated in the pain studies, the selective P2Y12 receptor antagonist PSB-0739 was most potent upon intrathecal application. P2Y12R mRNA and IL-1β protein were time-dependently overexpressed in the rat hindpaw and lumbar spinal cord following intraplantar CFA injection. This was accompanied by the upregulation of TNF-α, IL-6 and IL-10 in the hindpaw. PSB-0739 (0.3 mg/kg i.t.) attenuated CFA-induced expression of cytokines in the hindpaw and of IL-1β in spinal cord. Subdiaphragmatic vagotomy and the α7 nicotinic acetylcholine receptor antagonist MLA occluded the effect of PSB-0739 (i.t.) on pain behavior and peripheral cytokine induction. Denervation of sympathetic nerves by 6-OHDA pretreatment did not affect the action of PSB-0739. PSB-0739, in an analgesic dose, did not influence motor coordination and platelet aggregation. Genetic deletion of the P2Y12R in mice reproduced the effect of P2Y12R antagonists on mechanical hyperalgesia in inflammatory and neuropathic pain models, on acute thermal nociception and on the induction of spinal IL-1β. Here we report the robust involvement of the P2Y12R in inflammatory pain. The anti-hyperalgesic effect of P2Y12R antagonism could be mediated by the inhibition of both central and peripheral cytokine production and involves α7-receptor mediated efferent pathways.
    Neurobiology of Disease 06/2014; 70. DOI:10.1016/j.nbd.2014.06.011 · 5.20 Impact Factor
  • Source
    • "In addition to this, another pathway of communication between the nervous and immune systems, known as the vagal cholinergic anti-inflammatory pathway has been indentified. When the vagus nerve is activated by pro-inflammatory cytokines, it releases acetylcholine, which results in inhibition of the release of more pro-inflammatory mediators by macrophages [307] [308]. Experimental studies have shown that vagal nerve signaling inhibits the release of pro-inflammatory cytokines and improves outcomes following different models of ischemic stroke [308]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Stroke is a frequent cause of long-term disability and death worldwide. Ischemic stroke is more commonly encountered compared to hemorrhagic stroke, and leads to tissue death by ischemia due to occlusion of a cerebral artery. Inflammation is known to result as a result of ischemic injury, long thought to be involved in initiating the recovery and repair process. However, work over the past few decades indicates that aspects of this inflammatory response may in fact be detrimental to stroke outcome. Acutely, inflammation appears to have a detrimental effect, and anti-inflammatory treatments have been been studied as a potential therapeutic target. Chronically, reports suggest that post-ischemic inflammation is also essential for the tissue repairing and remodeling. The majority of the work in this area has centered around innate immune mechanisms, which will be the focus of this review. This review describes the different key players in neuroinflammation and their possible detrimental and protective effects in stroke. A better understanding of the roles of the different immune cells and their temporal profile of damage versus repair will help to clarify more effective modulation of inflammation post stroke.
    Current Medicinal Chemistry 12/2013; · 3.85 Impact Factor
Show more