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.
Highlights
Acetylcholine (ACh) is one of the old neurotransmitters identified in the central and peripheral nervous systems
Some secreted lymphocyte antigen-6/urokinase-type plasminogen activator (SLURP)-1+ cells in the tonsil interfollicular zone showed immunopositivity for CD205 (Figure 3A), a marker of mature dendritic cells (DCs) that mediates efficient antigen presentation [127], and these SLURP-1+ CD205+ DCs were surrounded by CD4+ T cells. These observations support the notion that ACh synthesized and released from T cells and activated macrophages during antigen presentation acts on α7 nAChRs expressed in immune cells, and that SLURP-1 potentiates the ACh activity at α7 nAChRs in both T cells and DCs [16, 126]
Ca2+-release activated Ca2+ (CRAC) channel blockade abolished Oxo-M-induced c-fos and IL-2 expression. These results suggest that activation of M3 or M5 mAChRs evokes IP3-mediated Ca2+ release from intracellular stores, leading to extracellular Ca2+ influx through CRAC channels, which generates repetitive [Ca2+]i oscillations and, in turn, enhances c-fos and IL-2 gene expression in T cells
Summary
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. 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 modulate antibody production. Evidence 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. We will review and discuss these issues in the context of the cholinergic system in immune cells
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