Adrenergic mechanisms in multiple sclerosis: the neuro-immune connection?

The role of adrenergic mechanisms in the modulation of the immune response is well established [1], and several lines of evidence point to their involvement in immune-mediated diseases of the nervous system such as multiple sclerosis (MS) [2]. Adrenoceptor ligands such as the β-adrenoceptor agonists terbutaline and isoproterenol [3] and the α-adrenoceptor antagonist prazosin [4] produce beneficial results in rats with experimental allergic encephalomyelitis (EAE), an established animal model of MS. Nonetheless, the rational basis for a therapeutic role of adrenoceptor ligands in MS has been hampered by the limited comprehension of the contribution of such mechanisms to human disease. The interesting article by De Keyser and co-workers, published recently in TiPS [5], discussed the involvement of β2-adrenoceptors expressed on astrocytes in inflammatory demyelination and axonal degeneration in MS, and provides novel insights into this intriguing topic. In this regard, we would like to add further points for consideration. First, noradrenaline acting on β2-adrenoceptors on astrocytes might be derived not only from noradrenergic nerve endings but also from activated lymphocytes infiltrating the CNS. Human peripheral lymphocytes express, following their activation, tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of catecholamines, and subsequently increase their intracellular content of dopamine, noradrenaline and adrenaline by up to 20–40-fold basal levels [6]. Intracellular catecholamines that accumulate in activated lymphocytes appear to be involved in the modulation of activation-induced apoptosis [7]. In addition, they provide these cells with a supply of mediators to be released following appropriate stimulation. Interestingly, interferon β (IFN-β), which is at least partially beneficial in MS, appears to be a strong inducer of catecholamine production and release from activated lymphocytes [8]. Although the relevance of this in vitro effect for the in vivo activity of IFN-β remains to be established, it cannot be excluded that this might contribute to a ‘restorative’ effect by IFN-β of the astrocyte–lymphocyte crosstalk. It would therefore be of interest to investigate the effects of IFN-β on β-adrenoceptor expression on astrocytes. Second, human lymphocytes express adrenoceptors, which might represent additional targets for noradrenaline, either released by nerve endings or derived from immune cells. In patients with MS, β2-adrenoceptor expression on lymphocytes: (i) is increased; (ii) correlates with magnetic resonance imaging (MRI) disease activity in primary progressive MS; and (iii) also occurs in the secondary progressive form of MS (although no relationship with MRI disease activity has been demonstrated) [9]. Increased production of cAMP has been detected in resting, but not activated, lymphocytes from MS patients following stimulation in vitro with β2-adrenoceptor agonists [10]. However, despite this phenomenon, reduced immunological responses to β2-adrenoceptor agonists appear to characterize lymphocytes from MS patients and from mice affected by EAE [11 and 12]. Biochemical deficiencies downstream of cAMP might therefore account for the aberrant signalling through β2-adrenoceptors in MS and EAE diseases, although these remain to be clearly elucidated [12]. The observation that IFN-β counteracts activation-induced reduction of β-adrenoceptor agonist-induced cAMP accumulation in human lymphocytes [13] might have interesting implications. It can therefore be proposed that in MS β2-adrenoceptor-dependent cAMP signalling might play a role not only in astrocytes, as pointed out by De Keyser and co-workers [5], but also in lymphocytes. In addition to β2-adrenoceptors, lymphocytes express a wide array of other G-protein-coupled receptors that, following stimulation, might modulate intracellular cAMP levels. In particular, dopamine D1- and D2-like receptors on lymphocytes mediate several of the immunomodulating effects of dopamine [14]. In this regard, we recently reported that impaired production of endogenous dopamine might occur in lymphocytes from MS patients with active disease [7], and that exogenous dopamine, acting through D1-like receptors, results in inhibition of the endogenous production of catecholamines [15] and reduction of apoptosis [16]. Further studies are needed to assess the interplay between exogenous and endogenous dopamine-mediated (and noradrenaline-mediated) signalling in lymphocytes, in addition to the possible differences in the effects of these transmitters in distinct cell subsets and under various functional conditions. Nonetheless, because anecdotal reports suggest that the catecholamine precursor -dihydroxyphenylalanine might be beneficial in MS patients [17] and exploratory clinical trials with dopaminergic and adrenergic agents have provided at least some encouraging results [18 and 19], studying noradrenaline-mediated and dopamine-mediated signalling in both CNS and immune system cells might provide further insight into the mechanisms that underlie the pathogenesis of MS and the scientific rationale for novel therapeutic strategies