Endogenous Catecholamines in Immune Cells: Discovery, Functions And Clinical Potential as Therapeutic Targets

Endogenous Catecholamines in Immune Cells: Discovery, Functions And Clinical Potential as Therapeutic Targets

The catecholamines dopamine, noradrenaline and adrenaline are well established neurotransmitters and neurohormones. Sympathoadrenergic pathways are pivotal to the communication between the nervous system and the immune system, and the role of dopaminergic pathways in the modulation of immune response is being increasingly unveiled. However, over the last two decades, evidence has accumulated regarding the ability of immune cells themselves to produce and utilize dopamine, noradrenaline and adrenaline. Endogenous catecholamines in immune cells represent a novel and emerging area of research with wide implications. As many dopaminergic and adrenergic agents are already in clinical use for several non-immune indications and with a usually favorable tolerability profile, this may represent an extremely attractive source of immunomodulating agents with significant therapeutic potential.

1. Physiology and pharmacology of catecholamines: an overview

Catecholamines are a family of chemical compounds containing a catechol or 3,4-dihydroxyphenyl group and an amine function. Dopamine, noradrenaline and adrenaline are the most abundant and important catecholamines in the human body and are all produced from l-tyrosine, a non-essential amino acid which is either obtained from dietary proteins or synthesized from the essential amino acid phenylalanine by the enzyme phenylalanine hydroxylase. l-tyrosine is converted to l-3,4-dihydroxyphenylalanine (l-DOPA) by tyrosine hydroxylase (TH, also known as tyrosine 3-monooxygenase, EC, which is the rate-limiting enzyme in the synthesis of catecholamines. The enzyme aromatic l-amino acid decarboxylase (EC, also known as DOPA decarboxylase) catalyzes the conversion of l-DOPA to dopamine. Noradrenaline is in turn synthesized from dopamine by dopamine β-hydroxylase (DBH, EC and is converted to adrenaline by phenylethanolamine N-methyltransferase (PNMT, EC (see Biosynthesis of dopamine, noradrenaline and adrenaline; Wikimedia Commons; Catecholamines biosynthesis Author: NEUROtiker, last accessed: 2 October 2013).

It has also been suggested that d-DOPA, the stereoisomer of l-DOPA, may be oxidized by the enzyme d-amino acid oxidase (DAO, EC and then converted to dopamine via an alternative biosynthetic pathway; however the relevance of this pathway remains to be established [1].

Dopamine and noradrenaline (and, to a lesser extent, adrenaline) act as neurotransmitters in the central nervous system (CNS). Noradrenaline is also the main neurotransmitter in postganglionic neurons on the sympathetic nervous systems, while adrenaline (and, to a lesser extent, noradrenaline) is the neurohormone secreted by chromaffin cells in the medulla of adrenal glands.

Dopamine: Four major dopaminergic pathways exist in the CNS: mesolimbic (associated with reward and learned behaviors), mesocortical (involved in cognitive functions including motivation, reward, emotion, and impulse control), nigrostriatal (affecting movement) and tuberoinfundibular (regulating prolactin secretion from the pituitary).

In the periphery, dopamine acts as paracrine/autocrine transmitter in the kidney, increasing natriuresis, renal blood flow and glomerular filtration. Circulating dopamine causes vasodilatation and reduced cardiac afterload, resulting in decreased blood pressure and increased cardiac contractility. Higher concentrations of dopamine however may act not only on dopaminergic receptors but also on β- and α-adrenoceptors (ARs): the former contribute to increased cardiac contractility while the latter result in vasoconstriction and increased blood pressure. Detailed information about anatomy, physiology and pharmacology of dopamine in the nervous system can be found in [2].

Noradrenaline and adrenaline: Noradrenaline and, to a lesser extent, adrenaline act as neurotransmitters in the CNS and in the peripheral nervous system. Chromaffin cells in medulla of adrenal glands also produce adrenaline (~80% in humans) and noradrenaline (~20%), which are directly released into the blood. In the CNS, the most important noradrenergic nucleus is the locus coeruleus (LC), from which axons project to the hippocampus, septum, hypothalamus and thalamus, cortex and amygdala, to the cerebellum, and also to the spinal cord. The LC is involved in attention, arousal and vigilance to external stimuli, and it regulates hunger by stimulating feeding behaviors. In the periphery, noradrenaline is the main transmitter of most autonomic sympathetic postganglionic fibers, and its main actions include: smooth muscle contraction in blood vessels supplying skin, kidney, and mucous membranes, stimulation of exocrine glands such as salivary and sweat glands, smooth muscle relaxation in the gut wall, bronchi and blood vessels supplying skeletal muscle, increased heart rate and force of contraction, as well as metabolic (increased glycogenolysis in liver and muscle, lipolysis in adipose tissue) and endocrine actions (modulation of insulin and renin secretion). Noradrenaline and adrenaline neurochemistry, anatomy and physiology are extensively discussed in [2].

1.1. Dopaminergic receptors

Receptors for dopamine, noradrenaline and adrenaline belong to the 7-transmembrane, G-protein coupled receptors family. Dopamine in particular acts on 5 different dopaminergic receptors (DRs) grouped into two families according to their pharmacological profile and main second messenger coupling: the D1-like (D1 and D5) which activate adenylate cyclase and the D2-like (D2, D3 and D4) which inhibit adenylate cyclase [3,4] (Table 1).

endogenous catecholamines lymphocytes Table 1DR ligands are currently used in the treatment of several non-immune conditions: agonists are used in the treatment of Parkinson’s disease, restless leg syndrome, and hyperprolactinemia, while antagonists are mainly used as antipsychotics and antiemetics. Physiopharmacology of DRs is summarized in Table 1, together with examples of DR ligands used in therapeutics, while detailed and continuously updated information about DR is provided in [4].

1.2. Adrenoceptors

Noradrenaline and adrenaline act on 9 different ARs, which include three major types – α1, α2 and β – each further divided into three subtypes [5] (Table 2).

endogenous catecholamines lymphocytes Table2AR agonists and antagonists are used to treat a variety of diseases, including hypertension, angina pectoris, congestive heart failure, asthma, depression, benign prostatic hypertrophy, and glaucoma. Additional conditions where AR ligands proved useful include shock, premature labor and opioid withdrawal, and as adjunct medications in general anesthesia. Physiopharmacology of α- and β-ARs together with examples of ligands used in therapeutics are listed in Table 2 and in Table 3, while detailed and continuously updated information is provided in [5].

endogenous catecholamines lymphocytes Table31.3. Modulation of dopaminergic and adrenergic pathways by indirectly acting agents

Besides classical receptor-targeted pharmacology, dopaminergic and adrenergic pathways offer a number of additional targets which include all the steps involved in catecholamine synthesis, storage and release, uptake and metabolism. Potential targets and examples of drugs already in use for non-immune indications (e.g. cardiovascular, neurologic, neuropsychiatric) are listed in Table 4.

endogenous catecholamines lymphocytes Table42. Dopaminergic and adrenergic modulation of immunity

The immune effects of dopamine as well as of noradrenaline and adrenaline have been the subject of several comprehensive reviews [6-14].

Adrenergic pathways modulating the immune response have been extensively investigated, since the identification of the sympathoadrenergic system as one of the two major pathways (the hypothalamic-pituitary-adrenal axis being the other one) responsible for the CNS-immune system cross-talk. In this context, sympathoadrenergic terminals release noradrenaline which acts on β2-ARs on immune cells inducing both inhibition of T helper (Th) 1 proinflammatory cytokines (e.g. IFN-γ, IL-12, TNF-α) and enhancement of Th2 cytokines (e.g. IL-10 and TGF-β), finally resulting in antiinflammatory effects [7,8]. Activation of β-ARs on human lymphocytes under specific conditions may however result also in stimulation of the immune response: for instance, noradrenaline may promote IL-12-mediated differentiation of naive CD4+ T cells into Th1 effector cells, and increase the amount of IFN-γ produced by Th1 cells [15]. Inhibitory β2-ARs are also expressed by monocytes/macrophages and neutrophils, as well as in CNS resident immune cells such as microglia and astrocytes. Proinflammatory responses may result also from activation of α1-ARs on human macrophages [16] or α2-ARs on rodent phagocytes [17], however in comparison to β-ARs, α-ARs in immune cells have so far received little consideration. A detailed review of adrenergic mechanisms modulating the immune response, including an extensive summary of α- and β-AR expression and function on cells of the innate and adaptive immune response, has been published recently [13].

Dopaminergic pathways in the modulation of immunity began only recently to receive specific attention [6,10,11,14]. Evidence exists that DR are expressed possibly in all human immune cells (including T and B cells, dendritic cells, macrophages, microglia, neutrophils and NK cells), and that immune cells can ‘meet’ dopamine in the brain as well as in blood, lymphoid organs and in several other peripheral tissues, such as the kidney and the liver (reviewed in [11]). Dopamine is also emerging as a regulator of dendritic cell and T cell physiology [18]. Based on available evidence, it has been proposed that dopamine may result in preferential activation of resting T cells and in inhibition of stimulated T cells [11]. For instance, in naive human T cells dopamine acts on DR D2/D3 receptors to induce β1 integrin-dependent adhesion to fibronectin [19], and on DR D2/D3 and D1/D5 receptors to increase TNF-α and IL-10 [20]. The effects of dopamine are likely specific for the various subsets of immune cells: for instance, in human CD4+CD25high T lymphocytes activation of D1-like receptors inhibits their ability to suppress the activity of effector T cells [21].

3. The discovery of endogenous catecholamines in immune cells

The first report showing the occurrence of endogenous catecholamines in immune cells dates back to 1994, when Jonas Bergquist and co-workers identified catecholamines and their metabolites in single lymphocytes and extracts of T- and B-cell clones by the use of capillary electrophoresis with electrochemical detection (a technique, at that time emerging, capable of rapidly determining multiple chemical species in pico-femtoliter biological samples). The endogenous origin of catecholamines was supported by pharmacological evidence showing that inhibition of TH reduced catecholamine levels, while the functional relevance of the observation was suggested by the ability of either dopamine or its precursor l-DOPA to inhibit in a concentration-dependent fashion lymphocyte proliferation and differentiation [22].

Two years before that, Georges J.M. Maestroni, working at the Center for Experimental Pathology in the Istituto Cantonale di Patologia of Locarno (CH), had reported for the first time that the sympathetic nervous system may modulate hematopoietic reconstitution after syngeneic bone marrow transplantation in mice [23]. Maestroni showed that chemical sympathectomy by 6-hydroxydopamine significantly increased the number of peripheral blood leukocytes after syngeneic bone marrow transplantation, and that AR ligands could modulate such effect. We met Georges Maestroni shortly after, in 1993, and our first collaborative paper was published in 1997, reporting the results of catecholamine measurement in the mouse bone marrow by means of HPLC with electrochemical detection, showing that dopamine, noradrenaline and adrenaline could be detected at this level and that noradrenaline was decreased by treatment with 6-hydroxydopamine and increased after pargyline, thus concluding that noradrenaline in the bone marrow originates mainly from sympathetic nerve endings and is metabolized through specific enzymatic pathways, while adrenaline and dopamine may originate from other sources [24]. Noradrenaline and dopamine in murine bone marrow exhibited a daily rhythmicity, with peak values occurring at night. The rhythm was disrupted by chemical sympathectomy, whereas adrenaline showed no rhythmicity or sensitivity to 6-hydroxydopamine. Noradrenaline (but not dopamine or adrenaline) was positively associated with the proportion of cells in the G2/M and S phases of the cell cycle [25]. After chemical sympathectomy catecholamine levels in the bone marrow were reduced but not abolished, an observation which prompted us to investigate their occurrence in both short-term and long-term bone marrow cultures as well as in human or murine B lymphoid cell lines, where all the three catecholamines were identified in significant amounts [25,26]. The obvious conclusion was that endogenous catecholamines in the bone marrow have both neural and cellular origins, therefore we started a systematic investigation of endogenous catecholamines in the immune system, with particular regard to human immune cells, by use of an HPLC method specifically adapted to the purpose [27] (Figure 1).

Shortly thereafter, we reported the occurrence of endogenous catecholamines in human peripheral blood mononuclear cells (PBMCs) [28] as well as in human granulocytes [29]. It was however a serendipitous observation which soon after led us to understand that TH-dependent catecholamine production in human lymphocytes could be hugely upregulated upon cell stimulation [30]. Increased production of catecholamines in activated lymphocytes led us to suggest a preferential involvement of catecholaminergic pathways in the functional modulation of activated cells and to propose that accumulated catecholamines could represent a supply of mediators to be released upon appropriate stimulation and which in turn may act upon lymphocytes themselves and/or upon neighboring cells [31]. In the following section, evidence so far available regarding the occurrence and the functional role of endogenous dopamine, noradrenaline and adrenaline in immune cells will be summarized and examined, and subsequently the relevance of such intrinsic dopaminergic and adrenergic pathways in the pathogenesis and progression of human disease as well as in the response to drug therapeutics will be discussed.

4. Presence of catecholamines in immune cells

4.1. Intracellular content and endogenous synthesis

Dopamine, noradrenaline and adrenaline (together with their major metabolites) have been identified and measured in several immune cell types, including: murine lymphocytes [32], peritoneal macrophages [33], bone marrow derived mast cells [34], splenic T and B cells [35], human peripheral blood mononuclear cells [28,30,36-38], various lymphocyte subsets [22,27], including CD4+CD25+ regulatory T lymphocytes [21], granulocytes [29], and hematopoietic cell lines [27]. Data concerning endogenous catecholamine levels and production in human immune cells are summarized in Table 5 and Table 6.

Catecholamines in immune cells are likely synthesized by the classical biosynthetic pathway (Figure 1), as indicated by the expression in both murine and human lymphocytes of the enzyme TH, the first and rate-limiting enzyme in the synthesis of catecholamines [30,35,39,40]. In human PBMCs, TH is strongly upregulated after cell activation, an event which occurs 6-8 h after the addition of phytohemagglutinin (PHA) and which is followed, after 48-72 h, by a sharp increase of intracellular catecholamines, which is prevented by the TH inhibitor a-methyl-p-tyrosine, as well as by the RNA-polymerase inhibitor actinomycin D and the protein synthesis inhibitor cycloheximide [30]. The expression and the activity of the other enzymes involved in the catecholamine biosynthetic pathway have been not yet fully characterized, although circumstantial evidence has been published regarding both DBH [41] and PNMT [42,43]. In rat splenic T and B cells a complex modulation of TH and PNMT expression and activity has been recently shown following stress exposure [35]. We recently identified DBH in human PBMCs by immunocytochemistry, close to the vesicular monoamine transporter (VMAT) type 2 as it could be expected in case the molecular organization of catecholamine storages in immune cells would resemble the neuronal ones (Cosentino M., De Bernardi S. and co-workers, unpublished data) (Figures 1).

The increase of intracellular catecholamines after mitogen stimulation occurs through protein kinase C activation and the contribution of intracellular Ca++-dependent mechanisms [30], and is in line with the reported upregulation of ARs occurring in lymphocytes following mitogen, glucocorticoid or proinflammatory cytokine treatment (see e.g. [44,45]) as well as with the upregulation of DRs after mitogen stimulation (Cosentino M., Kustrimovic N. and co-workers, unpublished data).

endogenous catecholamines lymphocytes Figure 4Figure 1. Expression of VMAT2 and DBH in human PBMCs. (Cosentino M., De Bernardi S. and co-workers, unpublished data)

Altogether, available evidence suggests a preferential involvement of intracellular catecholamine-operated pathways in activated immune cells, although differences are likely to occur among distinct cell subsets. For instance, we reported that in human peripheral blood mononuclear cells activated with PHA, the expression of TH mRNA as well as catecholamine production occurs only in T and B lymphocytes and is reduced by dopamine (but not by noradrenaline or adrenaline) through dopaminergic D1-like receptor-dependent mechanisms which include inhibition of TH gene transcription [46].

The proinflammatory cytokine IFN-γ exerts similar effects and its action is counteracted by IFN-β [47]. TH expression and catecholamine production are on the contrary enhanced by agents that induce catecholamine release (see below). Nonetheless, CD4+CD25high regulatory T lymphocytes, which are specialized T cells playing crucial roles in the control of immune homeostasis and express several surface markers of activation, also constitutively express TH and contain substantial amounts of dopamine, noradrenaline and adrenaline, together with ARs and DRs [21] (see section 5. for a detailed discussion about the functional role of intracellular catecholamines in different types of immune cells).

4.2. Storage and release

Agents able to effectively induce the release of catecholamines from human lymphocytes include reserpine [21,27,28], IFN-β [47] and elevation of extracellular K+ concentrations ([K+]e) [31]. Reserpine acts by irreversibly blocking VMAT [48]. In human cells there are two types of VMAT, VMAT1 and VMAT2, which are expressed in neural and neuroendocrine cells [49]. Preliminary evidence indeed suggests their occurrence also in immune cells and tissues such as rat thymus and spleen [50] and possibly also human peripheral blood lymphocytes [51]. Our group recently characterized the expression of VMAT2 in human PBMCs (Cosentino M., De Bernardi S. and co-workers, unpublished data) (Figures 3 and 4). Co-localization of DBH and VMAT2 suggests that intracellular compartments containing catecholamines in immune cells resemble those in synaptic terminals. DBH is specifically expressed in noradrenaline-containing neurons, and it is the only catecholamine-synthesizing enzyme localized within synaptic vesicles, where it occurs in both soluble and membrane-bound forms [52]. Synaptic-like vesicles have never been identified in immune cells, where nonetheless regulated secretion by means of specialized organelles has been extensively characterized in several cell types, including CD8+ T cells, NK cells as well as CD4+ T cells [53]. Interestingly, available information suggests that the molecular mechanisms of granule exocytosis in catecholamine-secreting chromaffin cells in the adrenal medulla and in cytotoxic T lymphocytes share many similar features [54].

Additional similarities between immune cells and neurons include the upregulation of TH expression and catecholamine production following catecholamine release [27,47], which is similar to the increased activity of neuronal catecholamine-synthesizing pathways following depletion with reserpine (see e.g. [55]).

endogenous catecholamines lymphocytes Table54.3. Catecholamine-metabolizing enzymes

Dopamine, noradrenaline and adrenaline are metabolized through monoamine oxidase (MAO)- and catechol-O-methyl transferase (COMT)-mediated pathways. Occurrence of both MAO and COMT in immune cells is indirectly suggested by the intracellular presence of all the main catecholamine metabolites [21,22,27-29,33,34,36,38] (Figure 2).

MAO activity in immune cells has been sometimes studied as a marker of neurodegenerative and neuropsychiatric disease [56,57]. MAO activity, predominantly of the B type, occurs in both human granulocytes and lymphocytes [58-60]. Support to its functional relevance has been provided mainly by use of pargyline, an irreversible MAO-B inhibitor, which leads to increased catecholamine levels in concanavalin A (Con A)-stimulated rodent lymphocytes [61], in human PBMCs [28] and in human granulocytes [29]. Recently, it has been reported that MAO-A is expressed in human monocytes in particular after incubation with IL-4, and that upregulation of MAO-A in these cells may contribute in switching naive monocytes into a resolving phenotype [62,63].

In comparison to MAO, investigations on COMT in immune cells have been so far very limited [64].

endogenous catecholamines lymphocytes Table64.4. Membrane transporters

Catecholamine membrane transporters include DAT (DopAmine Transporter) and NET (NorEpinephrine Transporter), both belonging to the solute carrier 6 (SLC6) gene family [65]. Interestingly, the affinity of noradrenaline and dopamine for NET and for DAT is about the same (see e.g. the PDSP Ki database – http://pdsp.med.unc.edu/pdsp.php), thus allowing sympathoadrenergic nerve terminals (which express NET but not DAT) to take up dopamine from the extracellular environment [66]. Evidence for the expression and the functional relevance of DAT in immune cells has been recently revised [67]. On the contrary, so far the only indirect evidence for the presence of NET in immune cells was provided nearly three decades ago, when Audus and Gordon [68] described a single population of desipramine-binding sites with an apparent dissociation constant (Kd) of about 0.4 nM in murine lymphocytes. Incubation of human PBMCs with the NET inhibitor desipramine or with the DAT inhibitor GBR 12909 results in increased extracellular levels of both dopamine and noradrenaline [28], an observation which is compatible with the occurrence of both transporters on the human lymphocyte membrane. Extensive evidence exists regarding the immunomodulating effects of monoamine uptake inhibitors (see e.g. [69]), however it remains to be established whether such effects may be attributed at least in part to a direct action on DAT and/or NET expressed on immune cells.

5. Functional role of immune cells-derived catecholamines

Experimental strategies to investigate the role of endogenous catecholamines in immune cells include: (i) interference with synthesis/degradation; (ii) interference with intracellular storage/release/uptake; (iii) effect of receptor blockade. Modulation of endogenous catecholamines can be obtained also by use of non-pharmacological approaches, e.g., suppression of expression of key proteins – TH, VMAT, etc. – by means of gene silencing techniques.

5.1. Innate immunity

Several lines of evidence suggest that endogenous noradrenaline and adrenaline subserve autocrine/paracrine regulatory loops in mouse peritoneal macrophages. Spengler et al. [33] showed that in these cells LPS-induced production of TNF-α was increased by the β-AR selective antagonist propranolol and decreased by the a2-AR selective antagonist idazoxan. In the same study intracellular noradrenaline was identified in mouse macrophages. Results were later confirmed by Chou et al. [70], who showed that the effect on TNF-α was even more pronounced in macrophages obtained from rats with streptococcal-cell-wall-induced arthritis. Evidence for endogenous catecholamines acting on α2-ARs was also reported in rodent phagocytes, where exposure to LPS resulted in catecholamine release together with induction of catecholamine-generating and degrading enzymes [17]. Blockade of α2-ARs or pharmacological inhibition of catecholamine synthesis suppressed lung inflammation in two rodent models of acute lung injury; while α2-AR agonist or inhibition of catecholamine-degrading enzymes induced increased inflammation [17] (see also section 5.3). Phagocytes from adrenalectomized rodents showed greatly enhanced catecholamine release together with increased expression of TH and DBH, and in these cells noradrenaline and adrenaline via α2-ARs seemed to directly activate NFκB, thus enhancing the release of TNF-α, IL-1β and IL-6 and the overall acute inflammatory response [71].

Recently, Gaskill et al. [72] showed that primary human monocyte-derived macrophages express mRNA for all the five subtypes of DRs, and that DR D3 and DR D4 are expressed on the plasma membrane. Monocyte-derived macrophages also express mRNA for DAT, VMAT2, TH and DOPA decarboxylase. DAT was shown to be expressed on the plasma membrane, VMAT2 on cellular membranes and TH and DOPA decarboxylase were in the cytosol. In the same study it was also shown that exogenous dopamine increased IL-6 and CCL2 production in unstimulated macrophages, and it increased IL-6, CCL2, CXCL8 and IL-10 and decreased TNF-α in LPS-stimulated macrophages [72]. Whether the same effect can be exerted by endogenous dopamine produced by macrophages however could only be indirectly inferred by published results.

5.2. Adaptive immunity

Endogenous catecholamines play a functional role also in cells of the adaptive immunity. In particular, in rodent lymphocytes Qiu et al. [73] reported that stimulation with Con A markedly increased both TH expression and catecholamine content, and that pharmacological inhibition of TH significantly enhanced Con A-induced IL-2 production. They concluded that endogenous catecholamines exert a tonic inhibition on the production of IL-2. Qiu et al. [61] subsequently showed that pharmacological inhibition of TH increased proliferation of rodent lymphocytes, which on the contrary was decreased by the MAO inhibitor pargyline. Pargyline also increased intracellular cAMP, the second messenger acted upon by β-ARs, and β-AR antagonists prevented the effect of pargyline, suggesting that the effect depended upon increased levels of catecholamines (likely, noradrenaline and/or adrenaline) in turn acting on β-ARs. Subsequently, the same group [74] isolated lymphocytes from the mesenteric lymph nodes of mice and stimulated the cells with Con A, showing that inhibition of TH with a-methyl-p-tyrosine reduced catecholamines both in lymphocytes and in supernatants, and upregulated expression of mRNAs and proteins of T-box expressed in T cells (T-bet) and IFN-γ but downregulated expression of mRNAs and proteins of GATA binding protein 3 (GATA-3) and IL-4. In contrast, pargyline increased intracellular and supernatant catecholamines and downregulated expression of T-bet and IFN-γ but upregulated expression of GATA-3 and IL-4. Similar results were obtained in CD4+ T lymphocytes isolated from the mesenteric lymph nodes of mice and transfected with recombinant TH miRNA expression vector (pcDNA6.2-GW/EmGFPmiR-TH) to inhibit the expression of TH [75], thus suggesting that catecholamines synthesized and secreted by lymphocytes regulate differentiation and function of Th cells, with an effect facilitating the shift of Th1/Th2 balance toward Th2 polarization.

As regards to human lymphocytes, Knudsen et al. [76] initially showed that intracellular levels of noradrenaline and adrenaline in circulating lymphocytes from healthy subjects strongly correlated with both basal and isoprenaline-stimulated intracellular cAMP. Variability in endogenous lymphocyte concentration of adrenaline also correlated with concomitant changes in the number of NK (CD3-CD56+) cells and cAMP in a subgroup of subjects [76]. Our group a few years later showed that in human stimulated PBMCs inhibition of catecholamine synthesis with a-methyl-p-tyrosine resulted in decreased activation-induced apoptosis [39]. Similar findings were subsequently obtained in rodent lymphocytes activated with Con A, where the proportion of apoptotic cells as well as the expression of apoptosis-related genes and proteins, Bax, Fas, Fas-Ligand and caspase-3 were decreased by a-methyl-p-tyrosine but increased by the MAO inhibitor pargyline, which on the contrary decreased the expression of the antiapoptotic protein Bcl-2 [77]. This effect was mediated by cAMP-PKA- and PLC-PKC-linked CREB-Smac/DIABLO pathways coupled to a1– and b2-ARs [78]. Among human lymphocytes, CD4+CD25high regulatory T cells, which are specialized T cells playing a key role in the control of immune homeostasis, have been shown to constitutively express TH and to contain substantial amounts of dopamine, noradrenaline and adrenaline, which are released upon treatment with reserpine. This suggests that catecholamines are stored in the cells by means of VMAT-dependent mechanisms, as indicated also by the presence of mRNA for both VMAT1 and 2 [21]. Functional experiments showed that catecholamine release in these cells results in reduced production of IL-10 and TGF-b, and in down-regulation of CD4+CD25high T cell-dependent inhibition of effector T lymphocyte proliferation, which occurs without affecting the production of TNF-a or IFN-g. Both CD4+CD25high T cells and effector T lymphocytes expressed on the cell membrane D1-like and D2-like DRs to a similar extent (12%-29% of the cells); however dopamine increased intracellular cAMP only in CD4+CD25high T cells. Catecholamine-dependent down-regulation of CD4+CD25high T cells was selectively reversed by pharmacological blockade of D1-like DRs, thus suggesting that in human CD4+CD25high T cells endogenous catecholamines subserve an autocrine/paracrine loop involving dopaminergic pathways and resulting in down-regulation of CD4+CD25high T cell regulatory functions [21].

5.3. Evidence from in vivo models

Flierl et al. [17] showed that in rats with acute lung injury stimulation of α2-ARs by either endogenous catecholamines or by exogenous agonists increased lung inflammation, which on the contrary was suppressed by α2-AR antagonists or inhibitors of catecholamine synthesizing enzymes. Findings were subsequently confirmed and extended in a rodent model of immune complex-induced acute lung injury, where it was also shown that the α2-AR-mediated increase of the severity of acute lung injury was enhanced by adrenalectomy [71]. Based on experimental evidence, it was suggested that the observed effect were dependent upon the catecholamines produced by phagocytic cells (neutrophils and macrophages) and in particular that both adrenaline and noradrenaline directly activate NFkB in macrophages, causing enhanced release of proinflammatory cytokines like TNF-α, IL-1β and IL-6.

In humans so far at least indirect evidence exists about the in vivo role of intracellular catecholamines in immune cells, in particular in multiple sclerosis (MS).

Peripheral blood lymphocyte levels of adrenaline seem to be higher in the first attack of MS whilst noradrenaline levels may be lower during remissions [79]. In stimulated lymphocytes from MS patients, no difference was observed in noradrenaline or adrenaline levels in comparison to cells from healthy controls, however cells from patients with chronic-progressive MS or relapsing-remitting MS in relapse produced less dopamine [39]. Endogenous catecholamines play a role in activation-induced apoptosis of lymphocytes [39], and the findings in cells from MS patients may thus be connected to the impairment of apoptotic mechanisms, possibly contributing to the survival of autoreactive cells in MS [80-83].

It was subsequently reported that in lymphocytes from MS patients treated with IFN-β for 12 months the production of catecholamines greatly increased and was less sensitive to IFN-γ-induced inhibition. Expression of mRNA for TH, β2-ARs and DR D5 was already enhanced after 1 month and further increased up to 6-12 months of treatment [84]. During treatment with IFN-β dopaminergic pathways in circulating lymphocytes likely shift from a prevalent D2-like DR operated modulation in untreated patients towards a prevalent D1-like DR modulation after IFN-β. These changes may be relevant for the therapeutic response in MS since D1-like DR D5 likely mediate the inhibitory effects of dopamine on proliferation and cytotoxycity in human CD4+ and CD8+ T cells [85], whereas activation of either the D2-like DR D2 or D3 may induce T cell proliferation and adhesion [19].

Interestingly, specific lymphocyte subsets may have different arrangements of dopaminergic pathways: for instance, D1-like DR (likely D5) play a role in the inhibition of human CD4+CD25high regulatory T cells, thus resulting in a “suppression of the suppressors” [21]. A recent study in MS patients undergoing treatment with IFN-β showed that, in comparison to cells from healthy subjects, CD4+CD25high T cells from untreated MS patients had increased mRNA for D1-like DR D5 and for TH. During treatment with IFN-β, both DR D5 and TH mRNA decreased down to values lower than those of cells from healthy controls. Most interestingly, in co-culture experiments, dopamine reduced the suppressive activity of CD4+CD25high T cells from healthy subjects and completely abolished the suppressive activity of cells from untreated MS patients. On the contrary, in cells from MS patients treated with IFN-β for 12 months dopamine had no more effects on their suppressive ability [86].

Such results likely indicate that in MS patients CD4+CD25high T cells have increased ability to produce dopamine (as suggested by increased TH mRNA), in turn suppressing their regulatory function (as indicated by both increased D1-like DR D5 mRNA expression and ability of dopamine to completely abolish ex vivo their regulatory function). Increased (endogenous) dopamine-operated inhibition of CD4+CD25high T cells likely contributes to the functional impairment of these cells in MS, resulting in enhanced disease activity [87,88], as also possibly suggested by the observation that TH mRNA levels after 12 months of IFN-β were significantly higher (on average 55%) in CD4+CD25high T cells from patients experiencing clinical relapses in comparison to those without relapses during the study [86].

From a general point of view, it seems that IFN-β induces a D1-like shift in immune cells of MS patients thus preparing these cells to respond to the potential antinflammatory action of endogenous dopamine and/or of dopaminergic agents (preferably selective for D1-like DRs). At the same time, IFN-β also reduces the D1-like DR-dependent (auto)-inhibitory loop on CD4+CD25high T regulatory cells, thus reducing the possibility that dopaminergic stimulation may result in the functional inhibition of these cells, an effect likely detrimental in MS. Overall, evidence points to the evaluation of dopaminergic agonists as add-ons to IFN-β in the treatment of MS, as a strategy to increase its therapeutic efficacy. A detailed discussion of adrenergic and dopaminergic modulation of immunity in MS has been recently published [14].

Endogenous production of catecholamines has been shown to occur also in inflamed synovial tissues of patients with rheumatoid arthritis (RA), where sympathetic innervation is reduced and local noradrenaline production is maintained by TH+ cells, mainly synovial macrophages (Miller et al., 2002). Noradrenaline levels correlate with the degree of inflammation and with spontaneous IL-8 secretion, while density of TH+ cells correlates positively with spontaneous secretion of IL-6, IL-8, and MMP-3 [89]. Further evidence for a critical role of local production of catecholamines by TH+ cells in RA synovium has been recently provided by showing that increased catecholamine release induced after blockade of VMAT2 with reserpine results in strong reduction of TNF (occurring through cAMP increase but possibly without involvement of classical β-ARs) and amelioration of inflammation in an animal model of RA [90]. Adrenergic mechanisms in the modulation of immune cells and their involvement in RA as well as in several other human diseases, including cancer, have been recently revised [14].

6. Concluding remarks

The ability of immune cells to synthesize and utilize dopamine, noradrenaline and adrenaline is now well established and significantly extends the well-known role of catecholamines in the neuroimmune cross-talk. Most importantly, intrinsic dopaminergic and adrenergic pathways in immune cells potentially represent an unprecedented opportunity for the specific and selective modulation of the immune response: indeed, the great number of potential pharmacological targets (including receptors, synthesizing and metabolising enzymes, transporters, etc.) is even exceeded by the availability of directly and indirectly acting pharmacological agents, already in clinical use for several non-immune indications and with a usually favourable therapeutic index (Tables 1-4). Dopaminergic and adrenergic agents actually represent an extremely attractive source of potentially novel immunomodulating agents with significant therapeutic potential.

Nonetheless, several key points still need to be clarified, before it will be possible to exploit at best the immunomodulatory activity of endogenous (and exogenous) dopaminergic and adrenergic agents [13,14] (see also Figure 2).

Endogenous catecholamines in immune cels discovery and functionFigure 2. The cellular network sustained by endogenous catecholamines in human lymphocytes. Speculative scheme depicting the possible actions of endogenous catecholamines produced and released by human lymphocytes in the development of the immune response. CD4+CD25high T regulatory cells (Treg) constitutively express TH, the key enzyme in the synthesis of catecholamines, DRs, α- and β-ARs, and contain high amounts of dopamine (DA), noradrenaline (NE), and adrenaline (E) stored in reserpine-sensitive compartments. Upon release, endogenous catecholamines (likely dopamine) subserve an autocrine/paracrine modulatory loop involving the activation of D1-like DR (D1/D5), leading to impaired suppressive activity of Treg towards mitogen-induced CD4+ T effector cells (Teff) proliferation. In the absence of stimulation, effector T lymphocytes express DRs, α- and β-ARs and contain trace amounts of DA, NE, and E. Upon stimulation, intracellular catecholamines increase by several ten-folds, and expression and function of both DRs and ARs undergo significant changes. Under these conditions, endogenous catecholamines may either directly affect cell survival and apoptosis from within the cell (lightnings), or they can be released (red arrows) to act upon lymphocytes themselves and/or upon neighbouring cells. Question marks (?) highlight various issues which await clarification. For the sake of clarity and simplicity, the picture does not include the potential role of catecholamines which are normally present into the extracellular space or which can be released from sympathoadrenergic terminals innervating lymphoid organs and tissues, or even which lymphocytes can encounter when they enter the brain in physiological (or pathological) situations. This figure was originally published in Blood. Cosentino M. et al. Human CD4+CD25+ regulatory T cells selectively express tyrosine hydroxylase and contain endogenous catecholamines subserving an autocrine/paracrine inhibitory functional loop. Blood. 2007; 109:632-642. ©The American Society of Hematology.

Outstanding questions include:

–     Catecholamine synthesis likely does not occur in all immune cells: which are the specific subsets and the functional conditions which trigger catecholamine production?

–     Does catecholamine production always include dopamine, noradrenaline and adrenaline or do “dopaminergic” and “adrenergic” immune cells actually exist?

–     Which are the catecholamine storage compartments and how is the releasing mechanism(s) regulated in the various immune cell populations? Which are the immune mediators stored and released together with catecholamines? Which are the physiological stimuli triggering catecholamine release from immune cells?

–     Adrenergic and dopaminergic receptors exist in multiple subtypes: are there cell subset-specific patterns of receptor expression? Which cell functions are controlled by each receptor in the various populations of immune cells?

In addition, when dealing with the role of catecholaminergic pathways in immune cells in disease conditions, it is necessary to consider that:

–     receptor dysregulation occurring in disease states is not only specific for the receptor type but also for the cell subset(s);

–     receptors may be acted upon not only by exogenous but also by endogenous catecholamines directly produced by immune cells (Figure 5);

–     dynamic changes occur to receptor expression and responsiveness (and to endogenous catecholamine production) during treatment with immunomodulatory drugs (e.g., the case of IFN-β in MS).

Last but not least, the pharmacological selectivity of adrenergic and dopaminergic agents must be carefully considered when choosing experimental drugs as well as when interpreting the resulting evidence: indeed, only well-constructed concentration-response curves and analysis of potency ratios of series of agonists and antagonists can provide consistent evidence for the involvement of specific receptor pathways.

The origin itself of neuroimmunology can be traced back to the identification of sympathoadrenergic pathways as the main channel of communication between the nervous system and the immune system [91]. Interestingly, nowadays the discovery of endogenous catecholamines in immune cells requires an in-depth revision of the role of such mediators in the neuroimmune network, which will also likely provide novel and original approaches for targeted immunomodulation.

Nonstandard Abbreviations:

AR, adrenoceptor; CNS, central nervous system; COMT, catechol-O-methyl transferase; DAO, d-amino acid oxidase; DAT, dopamine transporter; DBH, dopamine β-hydroxylase; DR, dopaminergic receptor; IFN, interferon; IL, interleukin; l-DOPA, l-3,4-dihydroxyphenylalanine; LC, locus coeruleus; LPS, lipopolysaccharide; MAO, monoamine oxidase; MS, multiple sclerosis; NET, norepinephrine transporter; NK, natural killer; PBMC, peripheral blood mononuclear cell; PHA, phytohemagglutinin; PNMT, phenylethanolamine N-methyltransferase; RA, rheumatoid arthritis; TGF, transforming growth factor; Th, T helper; TH, tyrosine hydroxylase; TNF, tumor necrosis factor; VMAT, vesicular monoamine transporter.

Authors’ affiliation

Marco Cosentino, Natasa Kustrimovic, Franca Marino – Center for Research in Medical Pharmacology, University of Insubria, Varese, Italy
Corresponding Author: Marco Cosentino, MD, PhD, E-mail: marco.cosentino@uninsubria.it


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