Close encounters of the monoamine kind: immune cells betray their nervous disposition

Abstract

Here we review the evidence for immune cells expressing multiple components of the serotonergic and dopaminergic systems that are more commonly associated with the central nervous system (CNS). We discuss where and how peripheral encounters with these biogenic monoamines occur and posit reasons as to why the immune system would wish to deploy these pathways. A full taxonomy of serotonergic and dopaminergic constituents and their workings in component cells of the immune system should facilitate the formulation of novel therapeutic approaches in diseases characterized by immune dysfunction and potentially provide a range of surrogate peripheral markers for registering and monitoring disturbances within the CNS.

Figures

Figure 1

5-HT stored in platelets or loaded into nerve fibres/cells within the circulation, skin, primary/secondary lymphoid tissues and even possibly the CNS is released on appropriate immune/inflammatory (stress/emotional?) activation. Immune cells exposed to 5-HT flow respond via receptors (up to 14 potentially, majority of which are 7-transmembrane domain (TMD) G-coupled proteins; 5-HT3 is a 4TMD cation ion channel) and/or the serotonin transporter, serotonin transporter (SERT; also a target for the SSRI antidepressants that block 5-HT uptake). Novel SERT-mediated signalling pathway recently described by Walther and colleagues in platelets (15) may also operate in immune cells where direct SERT-driven change has been shown (11, 13): transported 5-HT via transglutaminase (TGase) used to ‘serotonylate’ small GTPases such as RhoA and Rab4, both of which impact lymphocyte (and other immune cell) effector function.

Figure 2

Specific – receptor-mediated: Binding of the monoamine to dopamine receptors alters cAMP levels through modulation of adenylate cyclase (AC) – an enzyme to which these receptors couple (via stimulatory or inhibitory G-proteins). Activation of D1-like and D2-like receptors may inhibit T-lymphocyte activity (26) possibly via increases in cAMP levels (24). Co-activation of D1 and D2 dopamine receptors may initiate a unique signalling pathway, not activated by either D1 or D2 receptors alone (43). Alternatively, receptor ligation may initiate a signalling pathway that leads to oxidative stress (44). Specific – transporter-mediated: Dopamine can be actively internalised by cells that express the dopamine transporter (DAT). Intracellular dopamine may bind directly to cellular components such as GTPases to alter their activity (15) or enter the nucleus (45) and bind to nuclear elements (46) to alter transcriptional activity. Cellular dopamine can also chelate iron leading to cell cycle arrest (47). Inside the cell, dopamine can be metabolised by enzymes with the generation of reactive oxygen species (ROS) which may damage cellular components leading to cell-cycle arrest or death. Non-specific mechanisms: Extra-cellular dopamine can undergo auto-oxidation to generate quinones, semi-quinones and hydrogen peroxide (48). Quinones/semi-quinones may bind to thiol groups on cell-surface proteins and inhibit their activity. Hydrogen peroxide generation from dopamine is toxic to immunocytes (31, 37) possibly through the generation of superoxide and hydroxyl radicals which can damage lipids, proteins or DNA, culminating in cell cycle arrest or death.