Contributions of Non-Neuronal Cholinergic Systems to the Regulation of Immune Cell Function, Highlighting the Role of α7 Nicotinic Acetylcholine Receptors.

Loewi's discovery of acetylcholine (ACh) release from the frog vagus nerve and the discovery by Dale and Dudley of ACh in ox spleen led to the demonstration of chemical transmission of nerve impulses. ACh is now well-known to function as a neurotransmitter. However, advances in the techniques for ACh detection have led to its discovery in many lifeforms lacking a nervous system, including eubacteria, archaea, fungi, and plants.

Home transfusions are implemented using diverse approaches in Japan.

Background And Objectives: Japan's ageing society has increased the need for home healthcare, including home transfusions. We hence aimed to elucidate the purpose and utilization of home transfusions in Japan, which has not been clarified to date.

Materials And Methods: Clinics throughout Japan that provide home care and have experience in performing blood transfusions were surveyed.

GTS-21 Enhances Regulatory T Cell Development from T Cell Receptor-Activated Human CD4 T Cells Exhibiting Varied Levels of and Expression.

Immune cells such as T cells and macrophages express α7 nicotinic acetylcholine receptors (α7 nAChRs), which contribute to the regulation of immune and inflammatory responses. Earlier findings suggest α7 nAChR activation promotes the development of regulatory T cells (Tregs) in mice. Using human CD4 T cells, we investigated the mRNA expression of the α7 subunit and the human-specific dupα7 nAChR subunit, which functions as a dominant-negative regulator of ion channel function, under resting conditions and T cell receptor (TCR)-activation.

Management system of home transfusion in Japan: A nationwide survey in 2019.

Background And Objectives: In Japan, there are various opinions on the pros and cons of home transfusion because of safety concerns. We hence aimed to elucidate the safety and availability of home transfusion in Japan, which has not been clarified to date.

Materials And Methods: Clinics throughout Japan that provide home care and have experience in performing blood transfusions were surveyed.

Non-neuronal Cholinergic Muscarinic Acetylcholine Receptors in the Regulation of Immune Function.

Immune cells such as T and B cells, monocytes and macrophages all express most of the cholinergic components of the nervous system, including acetylcholine (ACh), choline acetyltransferase (ChAT), high affinity choline transporter, muscarinic and nicotinic ACh receptors (mAChRs and nAChRs, respectively), and acetylcholinesterase (AChE). Because of its efficient cleavage by AChE, ACh synthesized and released from immune cells acts only locally in an autocrine and/or paracrine fashion at mAChRs and nAChRs on themselves and other immune cells located in close proximity, leading to modification of immune function. Immune cells generally express all five mAChR subtypes (M-M) and neuron type nAChR subunits α2-α7, α9, α10, β2-β4.

Regulation of Immune Functions by Non-Neuronal Acetylcholine (ACh) via Muscarinic and Nicotinic ACh Receptors.

Acetylcholine (ACh) is the classical neurotransmitter in the cholinergic nervous system. However, ACh is now known to regulate various immune cell functions. In fact, T cells, B cells, and macrophages all express components of the cholinergic system, including ACh, muscarinic, and nicotinic ACh receptors (mAChRs and nAChRs), choline acetyltransferase, acetylcholinesterase, and choline transporters.

A historic perspective on the current progress in elucidation of the biologic significance of non-neuronal acetylcholine.

The "5 International Symposium on Non-neuronal Acetylcholine: from bench to bedside" was held on September 27-29, 2019 in Hyatt Regency, Long Beach, CA, USA. Approximately 50 scientists from 11 countries over 6 continents participated in this meeting. The major topics included an overall biologic significance of non-neuronal acetylcholine (ACh) and the roles of the non-neuronal cholinergic systems in mucocutaneous, respiratory, digestive, immunologic, endocrine, cardiovascular, musculoskeletal and kidney diseases, and cancer.

Minireview: Divergent roles of α7 nicotinic acetylcholine receptors expressed on antigen-presenting cells and CD4 T cells in the regulation of T cell differentiation.

α7 nAChRs expressed on immune cells regulate antigen-specific antibody and proinflammatory cytokine production. Using spleen cells from ovalbumin (OVA)-specific T cell receptor transgenic DO11.10 mice and the α7 nAChR agonist GTS-21, investigation of (1) antigen processing-dependent and (2) -independent, antigen presenting cell (APC)-dependent, naïve CD4 T cell differentiation, as well as (3) non-specific APC-independent, anti-CD3/CD28 mAbs-induced CD4 T cell differentiation, revealed the differential roles of α7 nAChRs expressed on T cells and APCs in the regulation of CD4 T cell differentiation.

α7 nAChRs expressed on antigen presenting cells are insensitive to the conventional antagonists α-bungarotoxin and methyllycaconitine.

Expression of α7 nicotinic acetylcholine receptors (nAChRs) on antigen presenting cells (APCs), such as macrophages and dendritic cells, is now well established. We have shown that GTS-21, a selective α7 nAChR agonist, downregulates APC-dependent CD4 T cell differentiation into regulatory T cells (Tregs) and effector Th1, Th2 and Th17 cells by inhibiting antigen processing, thereby interfering with antigen presentation. α7 nAChRs on Jurkat human leukemic T cells require functional T cell receptors (TCRs)/CD3 and leukocyte-specific tyrosine kinase to mediate nicotine-induced Ca-signaling via Ca release from intracellular stores, and are insensitive to two conventional α7 nAChR antagonists, α-bungarotoxin (α-BTX) and methyllycaconitine (MLA).

Distinct Roles of α7 nAChRs in Antigen-Presenting Cells and CD4 T Cells in the Regulation of T Cell Differentiation.

It is now apparent that immune cells express a functional cholinergic system and that α7 nicotinic acetylcholine receptors (α7 nAChRs) are involved in regulating T cell differentiation and the synthesis of antigen-specific antibodies and proinflammatory cytokines. Here, we investigated the specific function α7 nAChRs on T cells and antigen presenting cells (APCs) by testing the effect of GTS-21, a selective α7 nAChR agonist, on differentiation of CD4 T cells from ovalbumin (OVA)-specific TCR transgenic DO11.10 mice activated with OVA or OVA peptide (OVAp).

Expression and Function of the Cholinergic System in Immune Cells.

T and B cells express most cholinergic system components-e.g., acetylcholine (ACh), choline acetyltransferase (ChAT), acetylcholinesterase, and both muscarinic and nicotinic ACh receptors (mAChRs and nAChRs, respectively).

Physiological functions of the cholinergic system in immune cells.

T and B cells, macrophages and dendritic cells (DCs) all express most of the components necessary for a functional cholinergic system. This includes choline acetyltransferase (ChAT), muscarinic and nicotinic acetylcholine (ACh) receptors (mAChRs and nAChRs, respectively) and acetylcholinesterase (AChE). Immunological activation of T cells up-regulates cholinergic activity, including ChAT and AChE expression.

Acetylcholine released from T cells regulates intracellular Ca, IL-2 secretion and T cell proliferation through nicotinic acetylcholine receptor.

Aims: T lymphocytes synthesize acetylcholine (ACh) and express muscarinic and nicotinic ACh receptors (mAChR and nAChR, respectively) responsible for increases in the intracellular Ca concentration ([Ca]). Our aim in the present study was to assess whether autocrine ACh released from T lymphocytes regulates their physiological functions.

Main Methods: MOLT-3 human leukemic cell line and murine splenocytes were loaded with fura-2 to monitor [Ca] changes in the absence or presence of several AChR antagonists, including mecamylamine, methyllycaconitine and scopolamine.

CRAC channels are required for [Ca(2+)]i oscillations and c-fos gene expression after muscarinic acetylcholine receptor activation in leukemic T cells.

Aims: T lymphocytes express muscarinic acetylcholine receptors (mAChRs) involved in regulating their proliferation, differentiation and cytokine release. Activation of M1, M3 or M5 mAChRs increases the intracellular Ca(2+) concentration ([Ca(2+)]i) through inositol-1,4,5-phosphate (IP3)-mediated Ca(2+) release from endoplasmic reticulum Ca(2+) stores. In addition, T lymphocytes express Ca(2+)-release activated Ca(2+) (CRAC) channels to induce Ca(2+) influx and to regulate diverse immune functions.

IL-22/STAT3-Induced Increases in SLURP1 Expression within Psoriatic Lesions Exerts Antimicrobial Effects against Staphylococcus aureus.

Background: SLURP1 is the causal gene for Mal de Meleda (MDM), an autosomal recessive skin disorder characterized by diffuse palmoplantar keratoderma and transgressive keratosis. Moreover, although SLURP1 likely serves as an important proliferation/differentiation factor in keratinocytes, the possible relation between SLURP1 and other skin diseases, such as psoriasis and atopic dermatitis, has not been studied, and the pathophysiological control of SLURP1 expression in keratinocytes is largely unknown.

Objectives: Our aim was to examine the involvement of SLURP1 in the pathophysiology of psoriasis using an imiquimod (IMQ)-induced psoriasis model mice and normal human epidermal keratinocytes (NHEKs).

Recent progress in revealing the biological and medical significance of the non-neuronal cholinergic system.

This special issue of International Immunopharmacology is the proceedings of the Fourth International Symposium on Non-neuronal Acetylcholine that was held on August 28-30, 2014 at the Justus Liebig University of Giessen in Germany. It contains original contributions of meeting participants covering the significant progress in understanding of the biological and medical significance of the non-neuronal cholinergic system extending from exciting insights into molecular mechanisms regulating this system via miRNAs over the discovery of novel cholinergic cellular signaling circuitries to clinical implications in cancer, wound healing, immunity and inflammation, cardiovascular, respiratory and other diseases.

Transcriptional regulation of SLURP2, a psoriasis-associated gene, is under control of IL-22 in the skin: A special reference to the nested gene LYNX1.

A novel nicotinic acetylcholine (ACh) receptor (nAChR)-mediated transduction pathway, regulating keratinocyte function, has been elucidated in studies of secreted mammalian Ly6/urokinase plasminogen activator receptor-related protein (SLURP)-1 and -2. SLURPs are members of Ly6/neurotoxin superfamily (Ly6SF) of proteins containing the unique three-finger domain in their three-dimensional structure. Some endogenously expressed Ly6SF proteins (such as LYNX1, SLURP-1, and SLURP-2) modulate the function of nAChR, either as allosteric and/or orthosteric modulators, or as antagonists.

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

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.

SLURP-1, an endogenous α7 nicotinic acetylcholine receptor allosteric ligand, is expressed in CD205(+) dendritic cells in human tonsils and potentiates lymphocytic cholinergic activity.

Immune cells often express various nicotinic ACh receptor (nAChR) subtypes, including α7 nAChRs, as well as mRNA encoding secreted lymphocyte antigen-6/urokinase-type plasminogen activator receptor-related peptide (SLURP)-1, an endogenous α7 nAChR allosteric ligand. We detected SLURP-1 immunoreactivity in CD205(+) dendritic cells (DCs) residing in human tonsils. Phytohemagglutinin (PHA, 10 μg/ml), a T cell activator, attenuated cell proliferation and increased the ACh content of MOLT-3 human leukemic T cells compared with the vehicle control.

Effect of secreted lymphocyte antigen-6/urokinase-type plasminogen activator receptor-related peptide-1 (SLURP-1) on airway epithelial cells.

Acetylcholine (ACh) exerts various anti-inflammatory effects through α7 nicotinic ACh receptors (nAChRs). We have previously shown that secreted lymphocyte antigen-6/urokinase-type plasminogen activator receptor-related peptide-1 (SLURP-1), a positive allosteric modulator of α7 nAChR signaling, is down-regulated both in an animal model of asthma and in human epithelial cells treated with an inflammatory cytokine related to asthma. Our aim of this study was to explore the effect of SLURP-1, signal through α7 nAChR, in the pathophysiology of airway inflammation.

The missing link between long-term stimulation of nicotinic receptors and the increases of acetylcholine release and vasodilation in the cerebral cortex of aged rats.

In adult rats (4-9 months), chronic nicotine infusion increases the basal level of acetylcholine (ACh) release in the cerebral cortex and enhances responses of cortical ACh release and cortical vasodilation elicited by nucleus basalis of Meynert (NBM) stimulation. In the present study, we examined whether these effects of nicotine are detected in aged rats. Aged rats (27-30 months) received sustained subcutaneous nicotine (100 μg/kg/h) or saline for 14 days.

Localization of acetylcholine-related molecules in the retina: implication of the communication from photoreceptor to retinal pigment epithelium.

It has been long speculated that specific signals are transmitted from photoreceptors to the retinal pigment epithelium (RPE). However, such signals have not been identified. In this study, we examined the retinal expression and localization of acetylcholine-related molecules as putative candidates for these signals.

Reconciling neuronally and nonneuronally derived acetylcholine in the regulation of immune function.

Immune cells, including lymphocytes, express muscarinic and nicotinic acetylcholine (ACh) receptors (mAChRs and nAChRs, respectively), and agonist stimulation of these AChRs causes functional and biochemical changes in the cells. The origin of the ACh that acts on immune cell AChRs has remained unclear until recently, however. In 1995, we identified choline acetyltransferase mRNA and protein in human T cells, and found that immunological T cell activation potentiated lymphocytic cholinergic transmission by increasing ACh synthesis and AChR expression.

Critical roles of acetylcholine and the muscarinic and nicotinic acetylcholine receptors in the regulation of immune function.

Lymphocytes express both muscarinic and nicotinic acetylcholine (ACh) receptors (mAChRs and nAChRs, respectively), and stimulation of mAChRs and nAChRs produces various biochemical and functional changes. Although it has been postulated that parasympathetic cholinergic nerves directly innervate immune cells, no evidence has supported this hypothesis. We measured ACh in the blood of various animal species and determined its localization in T cells using a sensitive and specific radioimmunoassay.