Regulatory mechanisms of acetylcholine synthesis and release by T cells

Fujii, Takeshi; Takada‐Takatori, Yuki; Kawashima, Koichiro

doi:10.1016/j.lfs.2012.04.031

Cited by 41 publications

(44 citation statements)

References 13 publications

(17 reference statements)

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“…Activation of the ChAT-eGFP T cells increased the expression of eGFP suggesting that ChAT expression would likewise be increased under this condition. In fact, several other investigators had already established that ChAT mRNA, protein, and activity are upregulated when T cells are activated (Fujii et al, 1998; Fujii et al, 2008; Fujii et al, 2012b; Kawashima and Fujii, 2008). Subsequent studies by Ulloa and coworkers provided strong support for a T cell link between noradrenergic nerves and splenic macrophages, but their data implicated a different subgroup of helper T cells (Peña et al, 2011; Vida et al, 2011b).…”

Section: Vagal Anti-inflammatory Reflexmentioning

confidence: 99%

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Cholinergic modulation of the immune system presents new approaches for treating inflammation

Hoover

2017

Pharmacology & Therapeutics

240

169

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The nervous system and immune system have broad and overlapping distributions in the body, and interactions of these ubiquitous systems are central to the field of neuroimmunology. Over the past two decades, there has been explosive growth in our understanding of neuroanatomical, cellular, and molecular mechanisms that mediate central modulation of immune functions through the autonomic nervous system. A major catalyst for growth in this field was the discovery that vagal nerve stimulation (VNS) caused a prominent attenuation of the systemic inflammatory response evoked by endotoxin in experimental animals. This effect was mediated by acetylcholine (ACh) stimulation of nicotinic receptors on splenic macrophages. Hence, the circuit was dubbed the “cholinergic anti-inflammatory pathway”. Subsequent work identified the α7 nicotinic ACh receptor (α7nAChR) as the crucial target for attenuation of pro-inflammatory cytokine release from macrophages and dendritic cells. Further investigation made the important discovery that cholinergic T cells within the spleen and not cholinergic nerve cells were the source of ACh that stimulated α7 receptors on splenic macrophages. Given the important role that inflammation plays in numerous disease processes, cholinergic anti-inflammatory mechanisms are under intensive investigation from a basic science perspective and in translational studies of animal models of diseases such as inflammatory bowel disease and rheumatoid arthritis. This basic work has already fostered several clinical trials examining the efficacy of VNS and cholinergic therapeutics in human inflammatory diseases. This review provides an overview of basic and translational aspects of the cholinergic anti-inflammatory response and relevant pharmacology of drugs acting at the α7nAChR.

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Section: Vagal Anti-inflammatory Reflexmentioning

confidence: 99%

“…1). In fact, there is some evidence that ACh release from immune cells occurs by a non-vesicular mechanism involving a membrane hemichannel called mediatorphore (Fujii et al, 2012a; Fujii et al, 2012b). Lastly, T cell-derived ACh stimulates α7nAChRs on splenic macrophages to elicit the primary anti-inflammatory response.…”

Section: Vagal Anti-inflammatory Reflexmentioning

confidence: 99%

Cholinergic modulation of the immune system presents new approaches for treating inflammation

Hoover

2017

Pharmacology & Therapeutics

240

169

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“…So it is likely that the ACh is synthesized and probably released through a non-vesicular release mechanism. In fact the expression of mediatophore and organic cationic membrane transporter novel type 1 (OCTN-1) appear to be involved in non-vesicular acetylcholine release in different tissues including the immune cells [10,11,12]. …”

Section: Introductionmentioning

confidence: 99%

“…In fact, through “neuronal” and “non-neuronal cholinergic anti-inflammatory pathways”, mediated by the vagus nerve and immune cells respectively, ACh actively participates in the modulation of cytokine synthesis and release [13,14,15]. The cholinergic muscarinic and nicotinic receptors mediate ACh functions in immune cells modulating the release of pro- and anti-inflammatory cytokines, respectively [11]. …”

Section: Introductionmentioning

confidence: 99%

Dysregulated Homeostasis of Acetylcholine Levels in Immune Cells of RR-Multiple Sclerosis Patients

Bari

Reale

Nicola

et al. 2016

IJMS

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Multiple sclerosis (MS) is characterized by pro-inflammatory cytokine production. Acetylcholine (ACh) contributes to the modulation of central and peripheral inflammation. We studied the homeostasis of the cholinergic system in relation to cytokine levels in immune cells and sera of relapsing remitting-MS (RR-MS) patients. We demonstrated that lower ACh levels in serum of RR-MS patients were inversely correlated with the increased activity of the hydrolyzing enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Interestingly, the expression of the ACh biosynthetic enzyme and the protein carriers involved in non-vesicular ACh release were found overexpressed in peripheral blood mononuclear cells of MS patients. The inflammatory state of the MS patients was confirmed by increased levels of TNFα, IL-12/IL-23p40, IL-18. The lower circulating ACh levels in sera of MS patients are dependent on the higher activity of cholinergic hydrolyzing enzymes. The smaller ratio of ACh to TNFα, IL-12/IL-23p40 and IL-18 in MS patients, with respect to healthy donors (HD), is indicative of an inflammatory environment probably related to the alteration of cholinergic system homeostasis.

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“…This finding suggests immunological stimulation via TCR/CD3, such as occurs upon interaction of T cells with antigenpresenting cells, activates lymphocytic cholinergic activity. In addition to PHA, phorbol 12-myristate 13-acetate, a protein kinase C activator; A23187 or ionomycin, Ca 2+ ionophores; and dibutyryl cAMP (dbcAMP) all up-regulate ChAT mRNA expression and increase ACh synthesis in human leukemic T cell lines and human MNLs [43,44]. PHA-induced ChAT mRNA expression is inhibited by FK506, an immunosuppressant calcineurin inhibitor, which suggests the involvement of calcineurinmediated pathways in the regulation of ChAT transcription [44].…”

Section: Mechanisms Controlling Ach Synthesis In T Cellsmentioning

confidence: 99%

Non-neuronal cholinergic system in regulation of immune function with a focus on α7 nAChRs

Kawashima

Fujii

Moriwaki

et al. 2015

International Immunopharmacology

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In 1929, Dale and Dudley described the first reported natural occurrence of acetylcholine (ACh) in an animal's body. They identified this ACh in the spleens of horses and oxen, which we now know suggests possible involvement of ACh in the regulation of lymphocyte activity and immune function. However, the source and function of splenic ACh were left unexplored for several decades. Recent studies on the source of ACh in the blood revealed ACh synthesis catalyzed by choline acetyltransferase (ChAT) in CD4(+) T cells. T and B cells, macrophages and dendritic cells (DCs) all express all five muscarinic ACh receptor subtypes (mAChRs) and several subtypes of nicotinic AChRs (nAChRs), including α7 nAChRs. Stimulation of these mAChRs and nAChRs by their respective agonists causes functional and biochemical changes in the cells. Using AChR knockout mice, we found that M(1)/M(5) mAChR signaling up-regulates IgG(1) and pro-inflammatory cytokine production, while α7 nAChR signaling has the opposite effect. These findings suggest that ACh synthesized by T cells acts in an autocrine/paracrine fashion at AChRs on various immune cells to modulate immune function. In addition, an endogenous allosteric and/or orthosteric α7 nAChR ligand, SLURP-1, facilitates functional development of T cells and increases ACh synthesis via up-regulation of ChAT mRNA expression. SLURP-1 is expressed in CD205(+) DCs residing in the tonsil in close proximity to T cells, macrophages and B cells. Collectively, these findings suggest that ACh released from T cells along with SLURP-1 regulates cytokine production by activating α7 nAChRs on various immune cells, thereby facilitating T cell development and/or differentiation, leading to immune modulation.

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Regulatory mechanisms of acetylcholine synthesis and release by T cells

Cited by 41 publications

References 13 publications

Cholinergic modulation of the immune system presents new approaches for treating inflammation

Cholinergic modulation of the immune system presents new approaches for treating inflammation

Dysregulated Homeostasis of Acetylcholine Levels in Immune Cells of RR-Multiple Sclerosis Patients

Non-neuronal cholinergic system in regulation of immune function with a focus on α7 nAChRs

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