Vagus Nerve Activity Augments Intestinal Macrophage Phagocytosis via Nicotinic Acetylcholine Receptor α4β2

Zanden, Esmerij P. van der; Snoek, Susanne A.; Heinsbroek, Sigrid E. M.; Stanisor, Oana I.; Verseijden, Caroline; Boeckxstaens, Guy E.; Peppelenbosch, Maikel P.; Greaves, David R.; Gordon, Siamon; Jonge, Wouter J. de

doi:10.1053/j.gastro.2009.04.057

Cited by 118 publications

(94 citation statements)

References 33 publications

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“…Similarly, Morishita et al recently showed that electrical stimulation of the vagus nerve increased the β2 nicotinic receptors (β2nAChR) have indeed been detected on Mϕs, while a β2nAChR agonist inhibited ATP-induced Mϕs activation in the stomach (37). Similarly, α4β2 nicotinic receptor activation inhibits isolated intestinal and peritoneal Mϕs (38) and α5 nicotinic receptor knockout mice showed a significant worsening of disease compared with WT mice during colitis (39).…”

Section: Discussionmentioning

confidence: 99%

Vagotomy Affects the Development of Oral Tolerance and Increases Susceptibility to Develop Colitis Independently of α-7 Nicotinic Receptor

Giovangiulio

Bosmans

Meroni

et al. 2016

Mol Med

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Vagotomy (VGX) increases the susceptibility to develop colitis suggesting a crucial role for the cholinergic anti-inflammatory pathway in the regulation of the immune responses. Since oral tolerance and the generation of regulatory T cells (Tregs) are crucial to preserve mucosal immune homeostasis, we studied the effect of vagotomy and the involvement of α7 nicotinic receptors (α7nAChR) at the steady state and during colitis. Therefore, the development of both oral tolerance and colitis (induced by dextran sulfate sodium (DSS) or via T cell transfer) was studied in vagotomized mice and in α7nAChR -/-mice. VGX, but not α7nAChR deficiency, prevented oral tolerance establishment. This effect was associated with reduced Treg conversion in the lamina propria and mesenteric lymphnodes. To the same extent, vagotomized mice, but not α7nAChR -/-mice, developed a more severe DSS colitis compared with control mice treated with DSS, associated with a decreased number of colonic Tregs. However, neither VGX nor absence of α7nAChR in recipient mice affected colitis development in the T cell transfer model. In line, deficiency of α7nAChR exclusively in T cells did not influence the development of colitis induced by T cell transfer. Our results indicate a key role for the vagal intestinal innervation in the development of oral tolerance and colitis, most likely by modulating induction of Tregs independently of α7nAChR. online address: http://www.molmed.org

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Section: Discussionmentioning

confidence: 99%

Vagotomy Affects the Development of Oral Tolerance and Increases Susceptibility to Develop Colitis Independently of α-7 Nicotinic Receptor

Giovangiulio

Bosmans

Meroni

et al. 2016

Mol Med

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“…Finally, in which cell types is ␣4␤2 receptor anti-inflammatory signaling important? Previous in vivo evidence is restricted to certain peripheral macrophages (Matsunaga et al, 2001;van der Zanden et al, 2009), but the finding of ␣4* receptors on both neuronal and non-neuronal CNS cells raises the possibility that ␣4␤2 receptor mediated anti-inflammatory effects may occur in the brain (Gahring et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…Our findings point to a negative association between increases in ␣4␤2 receptor expression and down-regulation of PICs, which could account for the following: 1) loss of ␣4␤2 nAChRs observed in patients with neurological disorders, manifested by excess inflammation (Ripoll et al, 2004); in this case, PICs might be altering the assembly of nAChR subunits; and 2) although positron emission tomography and postmortem studies of the brains of long-term smokers reveal an appreciable increase in highaffinity binding sites for nicotine (Wü llner et al, 2008), longterm smokers with schizophrenia have lower inflammatory cytokines (IL-2 and IL-6) compared with their nonsmoking counterparts (Zhang et al, 2008). Therefore, the inverse correlation of smoking with development of neurological disorders might be due to a combination of the following: 1) nicotine up-regulates high-affinity ␣4␤2 receptors and their function, leading to cognitive and motor sensitization; and 2) nicotinic activation of ␣4␤2 and ␣7 receptors results in attenuation of anti-inflammatory responses (van der Zanden et al, 2009). …”

Section: Discussionmentioning

confidence: 99%

“…At concentrations achieved in smoker's blood, nicotine attenuates CNS inflammation as well as autoimmune responses in experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis . Furthermore, van der Zanden et al (2009) find that ␣4/␤2 nAChRs mediate cholinergic anti-inflammatory effects in certain peripheral macrophages. Whereas evidence for neural involvement in CNS cytokine regulation is still emerging, it is established that the vagus nerve activity regulates cytokine production in the periphery through activation of ␣7 nAChRs (Tracey, 2007).…”

Section: Introductionmentioning

confidence: 99%

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α4β2 Nicotinic Receptors Partially Mediate Anti-Inflammatory Effects through Janus Kinase 2-Signal Transducer and Activator of Transcription 3 but Not Calcium or cAMP Signaling

Hosur

Loring²

2010

Mol Pharmacol

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Despite evidence that smoking confers protection against neurological disorders, how and whether specific nicotinic receptor subtypes are involved is unknown. We reported previously that nicotine suppresses constitutive nuclear factor B (NF-B) activity and thereby proinflammatory cytokine (PIC) production in SHEP1 cells stably transfected with ␣4␤2 nicotinic receptors. Here, we report the anti-inflammatory effects of nicotine pretreatment in lipopolysaccharide (LPS)-stimulated SHEP1 cells. Nicotine (100 -300 nM, concentrations found in smoker's blood) blocked LPS-induced NF-B translocation and production of PICs interleukin (IL)-1␤ and IL-6 but only partially blocked inhibitor of nuclear factor-B␣ (IB␣) phosphorylation. These effects were exclusively in cells transfected with ␣4␤2 receptors but not in wild types. The cell-permeable calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,NЈ,NЈ-tetraacetic acid-acetoxymethyl ester, the adenylate cyclase stimulant forskolin, and a specific protein kinase A (PKA) inhibitor PKI 14-22-amide failed to block the effect of nicotine on LPS-induced NF-B translocation and IB␣ phosphorylation. However, the effects of nicotine on NF-B activity were significantly blocked by the highly specific janus kinase 2 (JAK2) inhibitor ␣-cyano-(3,4-dihydroxy)-N-benzylcinnamide (AG-490) and the signal transducer and activator of transcription 3 (STAT3) inhibitor 2-hydroxy-4- [[[[(4-methylphenyl)sulfonyl]oxy]acetyl]amino]-benzoic acid (NSC74859). These findings reveal a calcium-and cAMP-PKA-independent signaling cascade and suggest a role for JAK2-STAT3 transduction in ␣4␤2-mediated attenuation of LPS-induced inflammation. Anti-inflammatory effects of nicotine may therefore be mediated through ␣4␤2 receptors, the predominant high-affinity binding sites for nicotine in the central nervous system, in addition to the better-established ␣7 receptors.

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“…Before discussing these in more detail, it is of utmost importance to stress that dampening the immune response may have detrimental effects in case of infectious diseases. Although VN stimulation and nicotine increase intestinal macrophage phagocytosis, 58 reduced cytokine and chemokine production leads to impaired attraction and activation of neutrophils and T lymphocytes impairing bacterial clearance. In a model of bacterial peritonitis, α7nAChR knockout mice efficiently cleared the infection with Escherichia coli from their peritoneal cavity and had sterile blood cultures, whereas, wild-type animals had high bacterial loads at the primary site of infection and were bacteremic.…”

Section: Clinical Significance Of the Cholinergic Anti-inflammatory Pmentioning

confidence: 99%

The vagal innervation of the gut and immune homeostasis

Matteoli

Gomez‐Pinilla

Giovangiulio

et al. 2015

Autonomic Neuroscience

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The central nervous system interacts dynamically with the immune system to modulate inflammation through humoral and neural pathways. Recently, in animal models of sepsis, the vagus nerve (VN) has been proposed to play a crucial role in the regulation of the immune response, also referred to as the cholinergic anti-inflammatory pathway. The VN, through release of acetylcholine, dampens immune cell activation by interacting with α-7 nicotinic acetylcholine receptors. Recent evidence suggests that the vagal innervation of the gastrointestinal tract also plays a major role controlling intestinal immune activation. Indeed, VN electrical stimulation potently reduces intestinal inflammation restoring intestinal homeostasis, whereas vagotomy has the reverse effect. In this review, we will discuss the current understanding concerning the mechanisms and effects involved in the cholinergic anti-inflammatory pathway in the gastrointestinal tract. Deeper investigation on this counter-regulatory neuroimmune mechanism will provide new insights in the cross-talk between the nervous and immune system leading to the identification of new therapeutic targets to treat intestinal immune disease.

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Vagus Nerve Activity Augments Intestinal Macrophage Phagocytosis via Nicotinic Acetylcholine Receptor α4β2

Cited by 118 publications

References 33 publications

Vagotomy Affects the Development of Oral Tolerance and Increases Susceptibility to Develop Colitis Independently of α-7 Nicotinic Receptor

Vagotomy Affects the Development of Oral Tolerance and Increases Susceptibility to Develop Colitis Independently of α-7 Nicotinic Receptor

α4β2 Nicotinic Receptors Partially Mediate Anti-Inflammatory Effects through Janus Kinase 2-Signal Transducer and Activator of Transcription 3 but Not Calcium or cAMP Signaling

The vagal innervation of the gut and immune homeostasis

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