The dopaminergic system in autoimmune diseases

Abstract

Bidirectional interactions between the immune and the nervous systems are of considerable interest both for deciphering their functioning and for designing novel therapeutic strategies. The past decade has brought a burst of insights into the molecular mechanisms involved in neuroimmune communications mediated by dopamine. Studies of dendritic cells (DCs) revealed that they express the whole machinery to synthesize and store dopamine, which may act in an autocrine manner to stimulate dopamine receptors (DARs). Depending on specific DARs stimulated on DCs and T cells, dopamine may differentially favor CD4(+) T cell differentiation into Th1 or Th17 inflammatory cells. Regulatory T cells can also release high amounts of dopamine that acts in an autocrine DAR-mediated manner to inhibit their suppressive activity. These dopaminergic regulations could represent a driving force during autoimmunity. Indeed, dopamine levels are altered in the brain of mouse models of multiple sclerosis (MS) and lupus, and in inflamed tissues of patients with inflammatory bowel diseases or rheumatoid arthritis (RA). The distorted expression of DARs in peripheral lymphocytes of lupus and MS patients also supports the importance of dopaminergic regulations in autoimmunity. Moreover, dopamine analogs had beneficial therapeutic effects in animal models, and in patients with lupus or RA. We propose models that may underlie key roles of dopamine and its receptors in autoimmune diseases.

Keywords: Crohn’s disease; Th17; dendritic cell; multiple sclerosis; regulatory T cell; rheumatoid arthritis; systemic lupus erythematosus; ulcerative colitis.

Figure 1

Dopamine produced by dendritic cells and amplification of inflammation. Dendritic cells (DCs) express tyrosine hydroxylase (TH), which catalyzes the first step required for dopamine (DA) biosynthesis. However, since these cells do not express dopamine β-hydroxylase, the enzyme required to metabolize DA and to transform it into epinephrine and norepinephrine, they accumulate DA. DCs also express vesicular monoamine transporters 1 and 2 (VMAT) required to store DA in vesicular compartments. In response to antigen presentation or to LPS stimulation, DCs release DA from intracellular stores, which can modulate both DC physiology in an autocrine manner and CD4⁺ T cell responses in a paracrine fashion (not depicted). At certain concentrations, DC-derived DA interacts with DAR5 expressed by DCs, which promotes IL-23 production in response to LPS, and, thereby, enhances Th17 responses.

Figure 2

Altered CD4⁺ T cell programing by different dopamine concentrations. Effector CD4⁺ T cells lack the ability to synthesize DA, but may be exposed to DA produced by DCs, Tregs, or by other sources (not depicted). At intermediate DA concentrations, stimulation of DAR4 expressed by effector CD4⁺ T cells leads to cell quiescence by inducing expression of KLF2, a transcription factor that regulates T cell quiescence. At lower DA concentrations, stimulation of DAR3 expressed on DCs results, by means of an undefined mechanism, in heightened Th1 responses along with a reduction in Th17 immunity and a reduction of Th2-related cytokines.

Figure 3

Contrasted effects of dopamine produced by regulatory T cells. Tregs constitutively express TH and contain substantial amounts of DA. They also express VMAT-1 and VMAT-2, which allows them to accumulate DA in vesicular stores. In response to yet unknown physiological stimuli, Tregs release DA, which can interact with DARs expressed on the Treg cell surface, but also with DARs present on DCs and effector CD4⁺ T cells (not depicted). Treg-derived DA interaction with DAR1/5 expressed by Tregs, reduces the expression of IL-10 and TGF-β, and weakens the Treg’s suppressive activity exerted over effector CD4⁺ T cells.