Critical Neurotransmitters in the Neuroimmune Network

Abstract

Immune cells rely on cell-cell communication to specify and fine-tune their responses. They express an extensive network of cell communication modes, including a vast repertoire of cell surface and transmembrane receptors and ligands, membrane vesicles, junctions, ligand and voltage-gated ion channels, and transporters. During a crosstalk between the nervous system and the immune system these modes of cellular communication and the downstream signal transduction events are influenced by neurotransmitters present in the local tissue environments in an autocrine or paracrine fashion. Neurotransmitters thus influence innate and adaptive immune responses. In addition, immune cells send signals to the brain through cytokines, and are present in the brain to influence neural responses. Altered communication between the nervous and immune systems is emerging as a common feature in neurodegenerative and immunopathological diseases. Here, we present the mechanistic frameworks of immunostimulatory and immunosuppressive effects critical neurotransmitters - dopamine (3,4-dihydroxyphenethylamine), serotonin (5-hydroxytryptamine), substance P (trifluoroacetate salt powder), and L-glutamate - exert on lymphocytes and non-lymphoid immune cells. Furthermore, we discuss the possible roles neurotransmitter-driven neuroimmune networks play in the pathogenesis of neurodegenerative disorders, autoimmune diseases, cancer, and outline potential clinical implications of balancing neuroimmune crosstalk by therapeutic modulation.

Keywords: T cell neuroimmunology; cancer; dopamine; glutamate; immunotherapy; neurodegenerative disorders; serotonin; substance P.

Figure 1

Classical neuroimmune network. [Left] A feedback circuit exists between inflammatory cytokines and the hypothalamic-pituitary-adrenal (HPA) axis. Upon activation of the HPA axis and the release of adrenocorticotropic hormone (ACTH) following various physiologic or pathologic stress, adrenal cortex synthesizes glucocorticoids (GC) that can affect immune function by causing thymic involution, neutrophil (N) mobilization, eosinophil (Eo) accumulation, and myeloid and granulocyte differentiation, or polarize immune cells from inflammatory to tissue-protective non-inflamed phenotypes. GC upon binding with their receptors (GR) on macrophages (Mϕ) can switch their inflammatory cytokine secretions, such as TNFα, IFNγ and IL-1β, to tissue-protective types such as TGFβ and IL-10. [Right] Vagus nerve forms a synapse at the celiac ganglion with the adrenergic splenic nerve, which comes in contact with lymphocytes (Lym) expressing β2 adrenergic receptor (β2AR). Norepinephrine (NE) released from the adrenergic splenic nerve terminals activates β2AR that facilitates the synthesis of acetylcholine (ACh) from lymphocytes (33, 41). The ACh thus released activates the cognate α7 nicotinic ACh receptors (α7nAChR) on intrasplenic or extrasplenic myeloid cells. Signal transduction following ACh-induced activation of α7nAChR decreases nuclear translocation of the nuclear factor κ-light-chain-enhancer of activated B cells (NFκB), and inhibits inflammasome activity to reduce the production of inflammatory cytokines. This neuronal reflex circuit through the afferent vagus nerve, called cholinergic anti-inflammatory pathway, can attenuate the exacerbated “non-resolving inflammation” by suppressing accumulation of neutrophils and acting on Mϕ, dendritic cells (DC) and lymphocytes. It is also suggested that IL-1β receptors are present on vagal paraganglial glomus cells that can release neurotransmitters in response to hypoxemia, hypercapnia or acidosis. Downward arrows indicate a decrease in activity or number. Dotted lines indicate a feedback loop.

Figure 2

Dopamine-mediated cell-to-cell communication among immune cells. Dopamine (DA) can induce cytokine secretion and influence immune responses through activation of dopamine receptors, D_1-5. D₂ activation increases IL-10, D₃ activation triggers T cell secretion of TNFα and IFNγ, and D₅ activation stimulates TNFα and IL-10 secretion in T cells. D₁ and D₄ activation promotes T_H2 differentiation by increasing cAMP and transcription factor STAT5 and GATA3 activity. D₁ activation on B cells increases their expression of inducible T cell costimulatory ligand (ICOSL) and CD40L. Activation of D₁ and D₅ on regulatory T (T_reg) cells reduces their suppressive activity. Helper T (T_H) cells including T_reg cells can synthesize DA, store it in their vesicles expressing vesicular monoamine transporter (VMAT) and release it upon activation. Activation of D₃ on naïve CD8⁺T cells triggers their chemotactic migration. D₃ activation also facilitates effector CD8⁺T cell extravasation and adhesion to fibronectin. D₄ activation on primed CD8⁺T cells increases Krüpple-like factor-2 (KLF-2) activity to cause CD8⁺T cell quiescence. Activation of D₁ or D₂ receptors expressed on both macrophages (Mϕ) and dendritic cells (DC) promotes the secretion of cytokines such as IFNγ, TNFα, IL-1β, and IL-6. D₁ activation on DC promotes ERK, JNK and NFκB signaling, which induces cytokine production. D₁ activation also induces DC synthesis of DA during antigen presentation to T cells, consequently activating D₁ on CD8⁺T cells. Upward solid red arrows depict upregulation of indicated molecules or effects whereas the downward solid arrows indicate the reverse. Thin red line arrows indicate cells that produce DA.

Figure 3

Immune network of serotonin-mediated cell-to-cell communication. In mast cells, 5-HT_1A activation increases their migration and adhesion while 5-HT_1B, 5-HT_1D, and 5-HT_2A induces their degranulation and activity. 5-HT released from platelet (P) stores act upon myeloid and lymphoid cell subsets during inflammatory processes. As T cells differentiate, more 5-HT₇ are expressed together with 5-HT_1B and 5-HT_2A, increasing intracellular Ca²⁺. 5-HT₇ activation facilitates T cell proliferation through ERK1/2 phosphorylation and NFκB activation. 5-HT_1B and 5-HT_2A activation promotes T cell production of IL-2 and IFNγ and antigen-specific proliferation in T_H1 and CD8⁺ cytotoxic T lymphocytes (CTL). 5-HT_2A and 5-HT_2B activation promotes IL-17 production from CD4⁺T cells. 5-HT_1A activation has been implicated in decrease of CCR5, increase of CCL2 and MIP1α as well as phagocytosis by macrophages (Mϕ) while 5-HT_2A activation increases production of M2-type cytokines and migration. 5-HT signaling through 5-HT_1B, 5-HT_1E, 5-HT_2A, and 5-HT_2B increases intracellular Ca²⁺ in immature DCs. It also enhances DC maturation by upregulating cAMP levels through 5-HT₄ and 5-HT₇. Moreover, 5-HT₁, 5-HT₄, and 5-HT₇ activation on mature DCs promotes secretion of cytokines, such as IL-1β, IL-6, IL-8, and IL-10 whereas 5-HT₄ inhibits DC degranulation and production of IL-12 and TNFα. Upward solid red arrows depict upregulation of indicated molecules or effects whereas the downward solid arrows indicate the reverse. Thin red line arrows indicate cells that produce 5-HT.

Figure 4

Glutamate-mediated cell-to-cell communication among immune cells. Naïve human peripheral blood T cells express GluA3 and mGluR₅. Signaling through GluA3 increases Ca²⁺ influx, IL-2 secretion through negative membrane potential of a voltage-gated K⁺ channel K_v1.3, and IL-2 receptor upregulation during T cell activation. The activation is resisted by the increased expression of mGluR₅ on naïve T cells and by increased cAMP levels that inhibit Ras/ERK, JNKs, and NFκB and activate C-terminal Src kinase (CSK). Upon activation, T cells express GluN1/2B to sustain increased Ca²⁺ influx. The upregulation of GluN1/2B may downregulate GluA3, which is cleaved through granzyme B. Activation of mGluR_1/5 on effector T cells prevents the activation-induced cell death (AICD) by decreasing FasL expression. In activated T cells, mGluR₁ signaling increases PI3K and ERK1/2 signaling. mGluR1 activation also increases IFNγ, TNFα, IL-2, and IL-2R expression during T cell proliferation and effector differentiation, possibly through Glu released from mature DCs through their plasma membrane-expressed cystine-glutamate antiporter (xCT). DCs also express transmembrane excitatory amino acid transporters (EAAT) to regulate extracellular concentrations of Glu. Activation of mGluR1 on DCs facilitates the release of IL-6, IL-8, and CXCL1 production. Activation of both GluN1 and mGluR1 on CD4⁺T_H cells induces β-integrin-mediated adhesion to fibronectin and laminin as well as facilitates CXCR4-mediated chemotactic migration. GluN1 signaling causes T_H1 cell death but supports T_H2 responses. Upward solid red arrows depict upregulation of indicated molecules or effects whereas the downward solid arrows indicate the reverse. Thin red line arrows indicate cells that produce Glu.

Figure 5

Prospective neuroimmunotherapy scheme to optimize immune function in cancer and autoimmune pathologies. A crosstalk between immune cells and the central nervous system (CNS) has a bearing on human diseases. This offers treatment alternatives to mitigate cancer, neuropathologies and autoimmune diseases. The neurotransmitters present a high potential to act as therapeutic supplements to optimize the function of immune cells including eosinophils (Eo), neutrophils (N), macrophages (Mϕ), innate lymphoid cells (ILC), dendritic cells (DC), or T cells. Some immune cells such as platelets (P) serve as stores of neurotransmitters. Select neurotransmitter agonists or antagonists could be developed and tested in combination with other therapeutic modalities to suppress or stimulate immune responses, respectively. Such an optimized neuroimmunotherapy could be helpful in debilitating chronic immunopathologies. Activation of neurotransmitter receptors on lymphocytes by select neurotransmitters can modulate their migration and homing as well as differentiation, cytokine secretion, proliferation, survival, or effector function. As an example, adoptive T cell therapy for cancers can be improved by treating harvested tumor-infiltrating lymphocytes (TIL) with select neurotransmitter agonists or antagonists in vitro before transfer. Alternatively, neurotransmitter agonists or antagonists can be injected into the solid tumors to manipulate T cells or innate lymphoid cells (ILC) such as NK cells in situ. Optimization of such neuroimmunotherapy approaches could provide more effective holistic therapeutic benefits.