During last 15 years dopamine has emerged as a major regulator of inflammation. All
five dopamine receptors (DRs, DRD1-DRD5) have been found to be expressed in immune
cells where they exert a complex regulation of immunity [1]. Of note, DRs have been
found not only in cells of the adaptive immune system, but also in cells belonging
to the innate immunity, even including glial cells. The outcome of the dopamine effect
in the immune response depends in many factors, including differential expression
of DRs in the immune cells present in the inflamed tissue, the local levels of dopamine
and the signalling coupled to and the affinity of the different DRs involved. An increasing
number of studies analysing human cells in vitro or using in vivo approaches in animal
models have been unravelling and deciphering the complexity of dopaminergic regulation
of immunity. Integrating the knowledge acquired by these studies, the evidence have
indicated that stimulation of low-affinity DRs, for instance DRD1 and DRD2, are coupled
to anti-inflammatory mechanisms, thereby dampening inflammation [2, 3]. Conversely,
signalling triggered by high-affinity DRs, including DRD3 and DRD5, have been found
consistently to promote inflammation [4, 5].
It is noteworthy that tissues containing high-levels of dopamine in steady-state,
such as the nigrostriatal pathway or the gut mucosa, undergo a strong decrease of
dopamine levels during inflammation [1]. This fact involves a switch in the stimulation
of DRs: low-affinity DRs, which display anti-inflammatory properties and are stimulated
by high dopamine levels under homeostasis, are not longer stimulated during inflammatory
processes. Otherwise, signalling coupled to high-affinity DRs, which seems to be dampened
by low-affinity DRs stimulation under homeostasis, becomes dominant when dopamine
levels are reduced during inflammation. This idea highlight the relevance of high-affinity
DRs favouring the development and progression of inflammatory disorders and makes
these receptors key therapeutic targets.
Accordingly, DRD3, which display the highest affinity by dopamine, has been strongly
involved in favouring inflammation in several experimental systems. In this regard,
genetic and pharmacological evidence has indicated that DRD3-signalling constitutes
a potent regulator of CD4+ T-cell-mediated responses, including those implicated in
Parkinson’s disease [6] and inflammatory colitis [4], two pathologies that involve
a reduction of dopamine levels in the inflamed tissue (Figure 1). Mechanistic analyses
have revealed that DRD3-signalling in CD4+ T-cells induces suppressor of cytokine
signalling 5 in these cells, thus attenuating T-helper 2 (Th2) differentiation and
promoting Th1 responses. Moreover, evidence has also indicated that DRD3-signalling
favours Th17-immunity under chronic inflammatory conditions [4]. According to the
pivotal role of Th1 and Th17 inflammatory responses in the development of Parkinson’s
disease, we have recently demonstrated the therapeutic potential of DRD3- antagonism
in two different animal models, including 6-hydroxydopamine-induced and 1-methyl-4-phenyl-
1,2,3,6-tetrahydropyridine-induced Parkinson’s disease [7]. In those studies, DRD3-antagonism
not only reduced the neurodegenerative and neuroinflammatory process, but also attenuated
significantly the motor impairment associated to the loss of dopaminergic neurons.
Figure 1
Role of DRD3-signaling in CD4+ T-cells favouring Th1 and Th17 mediated responses in
disorders involving reduction of dopamine levels in the target tissue, such as Parkinson’s
disease and inflammatory bowel diseases.
Importantly, the therapeutic effect observed in Parkinson’s disease models in our
studies [7] was exerted by a highly-selective DRD3 antagonist, PG01037, displaying
the Ki values 0.70, 93.3 and 375 nM for DRD3, DRD2 and DRD4 respectively. In apparent
controversy with our recent findings, pramipexole, a drug described as a DRD3-agonist,
has been used for the symptomatic treatment of Parkinson’s disease. However, the range
of DRD3-selectivity for this drug is very limited, displaying Ki values of 0.5, 3.3,
3.9 and 3.9 nM for DRD3, DRD2S, DRD2L and DRD4 respectively. Thereby, it is likely
that at therapeutic concentrations pramipexole stimulates the dominant effects of
DRD2-signalling, abolishing DRD3- mediated effects.
Interestingly, the therapeutic effect of DRD3- antagonism seems to be beyond of targeting
DRD3 confined to CD4+ T-cells. Our analyses performed in glial cells have suggested
that DRD3-deficiency gives an anti-inflammatory behaviour to astrocytes, which results
in attenuated microglial activation in a model of Parkinson’s disease [7]. Furthermore,
recently we found that DRD3-deficiency or DRD3-antagonism in dendritic cells results
in an exacerbated stimulation of CD8+ T-cell-mediated immunity, strengthening the
immune response against tumours [8]. Mechanistic analyses indicated that the inhibition
of DRD3-signalling in dendritic cells promotes an increase in antigen cross-presentation
in class I MHC molecules to CD8+ T-cells, thereby potentiating the development of
cytotoxic T-lymphocytes. Thus, emerging evidence indicates DRD3 as a key therapeutic
target with a dual potential: whereas DRD3-inhibtion attenuates inflammation in pathologies
associated to reduction of dopamine levels and CD4+ T-cell-mediated responses (Figure
1), blocking DRD3-signalling in dendritic cells may improve the outcome of disorders
that involve insufficient cytotoxic T-lymphocyte-responses, such as cancer.