Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
, 8, 1085
eCollection

Expression and Function of the Cholinergic System in Immune Cells

Affiliations
Review

Expression and Function of the Cholinergic System in Immune Cells

Takeshi Fujii et al. Front Immunol.

Abstract

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). Using ChATBAC-eGFP transgenic mice, ChAT expression has been confirmed in T and B cells, dendritic cells, and macrophages. Moreover, T cell activation via T-cell receptor/CD3-mediated pathways upregulates ChAT mRNA expression and ACh synthesis, suggesting that this lymphocytic cholinergic system contributes to the regulation of immune function. Immune cells express all five mAChRs (M1-M5). Combined M1/M5 mAChR-deficient (M1/M5-KO) mice produce less antigen-specific antibody than wild-type (WT) mice. Furthermore, spleen cells in M1/M5-KO mice produce less tumor necrosis factor (TNF)-α and interleukin (IL)-6, suggesting M1/M5 mAChRs are involved in regulating pro-inflammatory cytokine and antibody production. Immune cells also frequently express the α2, α5, α6, α7, α9, and α10 nAChR subunits. α7 nAChR-deficient (α7-KO) mice produce more antigen-specific antibody than WT mice, and spleen cells from α7-KO mice produce more TNF-α and IL-6 than WT cells. This suggests that α7 nAChRs are involved in regulating cytokine production and thus modulate antibody production. Evidence also indicates that nicotine modulates immune responses by altering cytokine production and that α7 nAChR signaling contributes to immunomodulation through modification of T cell differentiation. Together, these findings suggest the involvement of both mAChRs and nAChRs in the regulation of immune function. The observation that vagus nerve stimulation protects mice from lethal endotoxin shock led to the notion of a cholinergic anti-inflammatory reflex pathway, and the spleen is an essential component of this anti-inflammatory reflex. Because the spleen lacks direct vagus innervation, it has been postulated that ACh synthesized by a subset of CD4+ T cells relays vagal nerve signals to α7 nAChRs on splenic macrophages, which downregulates TNF-α synthesis and release, thereby modulating inflammatory responses. However, because the spleen is innervated solely by the noradrenergic splenic nerve, confirmation of an anti-inflammatory reflex pathway involving the spleen requires several more hypotheses to be addressed. We will review and discuss these issues in the context of the cholinergic system in immune cells.

Keywords: SLURP-1; dendritic cell; lymphocyte; mAChR; macrophage; nAChR.

Figures

Figure 1
Figure 1
Expression of choline acetyltransferase (ChAT) mRNA and protein in human immune cells. (A1) Western blot analysis of ChAT protein expression in MOLT-3 human leukemic T cells. (A2) Expression of ChAT mRNA detected using reverse transcription-polymerase chain reaction (RT-PCR). NC, negative control of MOLT-3 without RT. Arranged from study by Fujii et al. (33). (B) Expression of ChAT mRNA in human CD4+ T cells and its potentiation by immunological activation with phytohemagglutinin (PHA). Note that CD8+ T cells do not express ChAT mRNA, even after immunological activation. RT, reverse transcriptase. Arranged from study by Fujii et al. (34).
Figure 2
Figure 2
Expression of genes for mAChRs and nAChR α subunits in immune cells from C57BL/6J mice. (A) mRNA expression of mAChR subtypes detected using reverse transcription-polymerase chain reaction. MNLs, mononuclear leukocytes; DCs, dendritic cells. GAPDH, glyceraldehyde-3-phosphate dehydrogenase. (B) mRNA expression of nAChR α subunits. Arranged from study by Kawashima et al. (36).
Figure 3
Figure 3
Immunohistochemical staining of SLURP-1, CD205, CD4, and CD68 in human tonsils. (A) Merged image showing SLURP-1 (green) and CD205 (red) immunoreactivities in the interfollicular zone. Note that some CD205+ cells were also SLURP-1+. An enlarged image of the boxed area is shown in the lower panel. (B) Merged image showing SLURP-1 (green) and CD4 (red) immunoreactivities in the interfollicular zone. Note that the SLURP-1+ cells are surrounded by CD4+ T cells. An enlarged image of the boxed area is shown in the lower panel. (C) Merged image showing SLURP-1 (green) and CD68 (red) immunoreactivities in the interfollicular zone. Note that the SLURP-1+ cells are located in close proximity to CD68+ macrophages. An enlarged image of the boxed area is shown in the lower panel. Arranged from data by Fujii et al. (126).
Figure 4
Figure 4
Role for α7 nAChRs during differentiation of naïve T cells. (A) Schematic drawing of non-specific activation of naïve T cell differentiation via T cell receptor and CD28 in the presence of GST-21, a partial agonist for α7 nAChRs. Differentiation of naïve CD4+ T cells into effector T cells (Th1, Th2, and Th17) and regulatory T cells (Tregs) is dictated by the presence of cytokines shown on the respective arrows (142, 143). GTS-21 may facilitate the expression of transcription factor FoxP3 or TGF-β leading to Treg expansion. IFN-γ, interferon-γ; IL-4, interleukin-4; IL-6, interleukin-6; IL-12, interleukin-12; IL-17, interleukin-17; TGF-β, transforming growth factor-β. (B) Effects of GST-21 on naïve T cell differentiation in α7 nAChR-deficient (α7-KO) and wild-type (WT) mice. Note that GTS-21 upregulated differentiation into Tregs in the WT, but not α7-KO mice. Th1 differentiation was not affected by GTS-21 in the both genotypes. Arranged from study by Kawashima et al. (141).
Figure 5
Figure 5
Schematic drawing of the efferent signaling pathway of the inflammatory reflex in the context of the cholinergic system in immune cells. ChAT+ T cell interaction with antigen peptides loaded on MHC class II on dendritic cells (DCs) or macrophages via the TCR/CD3 complex, CD80/CD86 (B7) co-stimulatory molecules with CD28, and ICAM-1/ICAM-2 with LFA-1, increases the synthesis and release of ACh from T cells [see a review by Fujii et al. (16)]. Inflammatory mediators induce the release of the positive allosteric α7 nAChR ligand SLURP-1 from SP/CGRP-containing sensory fibers. Efferent inflammatory reflex signaling via the vagus nerve may also induce released SLURP-1 from SP+/CGRP+ fibers in the spleen. This released SLURP-1, as well as SLURP-1 released from CD205+ mature DCs, potentiates the action of ACh from ChAT+ CD4+ T cells at α7 nAChRs on macrophages, thereby suppressing synthesis and release of tumor necrosis factor (TNF)-α. The model proposed here is from reviews by Kawashima et al. (111) and Fujii et al. (16). Green rectangles depict SLURP-1. Red ellipses depict acetylcholine. AcCoA, acetyl coenzyme A; ICAM-1, intercellular adhesion molecule-1; ICAM-2, intercellular adhesion molecule-2; LFA-1, lymphocyte function-associated antigen-1; LPS, lipopolysaccharide; MHC II, major histocompatibility complex class II; SLURP-1, secreted lymphocyte antigen-6/urokinase-type plasminogen activator receptor-related peptide-1; TCR, T cell receptor; TLR, toll-like receptor.

Similar articles

See all similar articles

Cited by 21 articles

See all "Cited by" articles

References

    1. Burgen AS. The background of the muscarinic system. Life Sci (1995) 56(11–12):801–6.10.1016/0024-3205(95)00013-V - DOI - PubMed
    1. Ewins AJ. Acetylcholine, a new active principle of ergot. Biochem J (1914) 8(1):44–9.10.1042/bj0080044 - DOI - PMC - PubMed
    1. Dale HH. The action of certain esters and ethers of choline, and their relation to muscarine. J Pharmacol Exp Ther (1914) 6:147–90.
    1. Loewi O. Über humorale Übertragbarkeit der Herznervenwirkung. Pflugers Arch Gesamte Physiol Menschen Tiere (1921) 189:239–42.10.1007/BF01741929 - DOI
    1. Loewi O, Navratil E. Über humorale Übertragbarkeit der Herznervenwirkung. X. Mitteilung: Über das Schicksal des Vagusstoffs. Pflugers Arch Gesamte Physiol Menschen Tiere (1926) 214:678–88.10.1007/BF01741946 - DOI
Feedback